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1. Tick-Borne Encephalitis in Auvergne-Rhône-Alpes Region, France, 2017–2018

Author: Gilda Grard, Paul O. Verhoeven, Sylvie Pillet, Elisabeth Botelho-Nevers, Claire Bretagne, M. Guerbois-Galla, Sylvie Gonzalo, Alexandra Mailles, Samira Fafi-Kremer, Isabelle Leparc-Goffart, Aurélie Velay, Bruno Pozzetto, Amandine Gagneux-Brunon, Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, INSB-INSB-Centre National de la Recherche Scientifique (CNRS), Université de Saint-Etienne, Virology Laboratory, General Hospital Papageorgiou, Institut de Recherche Biomédicale des Armées [Antenne Marseille] (IRBA), Unité des Virus Emergents (UVE), Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Référence des Arbovirus [Marseille], Institut de Recherche Biomédicale des Armées [Antenne Marseille] (IRBA)-Unité d'Arbovirologie [Marseille], Hôpital d'Instruction des Armées Laveran, Service de Santé des Armées-Service de Santé des Armées-Hôpital d'Instruction des Armées Laveran, Service de Santé des Armées-Service de Santé des Armées, Université de Picardie Jules Verne (UPJV), Département des maladies infectieuses, Institut de Veille Sanitaire (INVS), Groupe Immunité des Muqueuses et Agents Pathogènes (GIMAP), Université Jean Monnet [Saint-Étienne] (UJM), CHU Saint-Etienne, Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Institut des sciences biologiques (INSB-CNRS)-Institut des sciences biologiques (INSB-CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Jean Monnet - Saint-Étienne (UJM), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), and BUISINE, Soline
Subjects: Male, tickborne encephalitis, Epidemiology, vector-borne infections, lcsh:Medicine, TBE, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, 030212 general & internal medicine, tickborne encephalitis virus, Child, ComputingMilieux_MISCELLANEOUS, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, biology, Lyme borreliosis, Tick-Borne Encephalitis in Auvergne-Rhône-Alpes Region, France, 2017–2018, tick-borne encephalitis, Dispatch, 3. Good health, Tick-borne encephalitis virus, Infectious Diseases, Geography, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, France, Encephalitis, Tick-Borne, Encephalitis, Microbiology (medical), tick-borne encephalitis virus, 030231 tropical medicine, Tbe virus, Encephalitis Viruses, Tick-Borne, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, medicine, Animals, Humans, emergence, Serologic Tests, viruses, lcsh:RC109-216, Aged, Ixodes, lcsh:R, Tick-borne encephalitis, medicine.disease, biology.organism_classification, bacterial infections and mycoses, Virology
Abstract: Three autochthonous cases of tick-borne encephalitis (TBE) acquired in rural areas of France where Lyme borreliosis, but not TBE, is endemic highlight the emergence of TBE in new areas. For patients with neurologic involvement who have been in regions where Ixodes ticks circulate, clinicians should test for TBE virus and other tickborne viruses.
Published: 2019

2. SARS-CoV-2 Pneumonia in Hospitalized Asthmatic Patients Did Not Induce Severe Exacerbation

Author: Frédéric de Blay, Aissam Labani, Julien Godet, Thi Cam Tu Hoang, Carine Metz-Favre, Loic Kassegne, Philippe Fraisse, Benjamin Renaud-Picard, C. Marcot, Ines Abessolo-Amougou, M. Grandbastien, Guillaume Pamart, Samira Fafi-Kremer, Irina Enache, N. Khayath, Virginie Doyen, Pierre Leyendecker, Carole Ederle, Anays Piotin, Louise Manien, Romain Kessler, Marianne Riou, CHU Strasbourg, Fédération Hospitalo-Universitaire (OMICARE), Centre de Recherche d’Immunologie et d’Hématologie [Strasbourg], Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Centre Hospitalier Universitaire Brugmann [Bruxelles] (CHU), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and CCSD, Accord Elsevier
Subjects: Male, Exacerbation, [SDV]Life Sciences [q-bio], Aucun, Comorbidity, medicine.disease_cause, Severity of Illness Index, law.invention, 0302 clinical medicine, exacerbation, law, immune system diseases, ACE2, Angiotensin Converting Enzyme 2, Immunology and Allergy, 030212 general & internal medicine, Coronavirus, qRT-PCR, quantitative real-time Reverse Transcriptase PCR, Adrenergic beta-Agonists, Middle Aged, Intensive care unit, 3. Good health, [SDV] Life Sciences [q-bio], Hospitalization, Europe, Intensive Care Units, COVID-19, Coronavirus Disease 2019, Female, France, Coronavirus Infections, medicine.medical_specialty, Pneumonia, Viral, SARS-CoV-2 pneumonia, FEV1, Flow Expiratory Volume in one second, Article, 03 medical and health sciences, Betacoronavirus, Internal medicine, ICU, Intensive Care Unit, Severity of illness, medicine, Humans, FVC, Flow Volume Capacity, Glucocorticoids, Pandemics, Asthma, Aged, Retrospective Studies, business.industry, SARS-CoV-2, COVID-19, Retrospective cohort study, COPD, Chronic Obstructive Pulmonary Disease, asthma, medicine.disease, Respiration, Artificial, respiratory tract diseases, Pneumonia, SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2, 030228 respiratory system, Socioeconomic Factors, BMI, Body Mass Index, business
Abstract: Background Viral infections are known to exacerbate asthma in adults. Previous studies have found few asthmatics among SARS-CoV-2 pneumonia cases. However, the relationship between SARS-CoV-2 infection and severe asthma exacerbation is not known. Objective We assessed the frequency of asthma exacerbation in asthmatic patients hospitalized for SARS-CoV-2 pneumonia and compared symptoms laboratory and radiological findings in asthmatic and non-asthmatic patients with SARS-CoV-2 pneumonia. Methods We included 106 patients between March 4 and April 6, 2020, who were hospitalized in the Chest Diseases Department of Strasbourg University Hospital; 23 were asthmatics. To assess the patients’ asthma status, three periods were defined: the last month before the onset of COVID-19 symptoms (p1), pre-hospitalization (p2) and during hospitalization (p3). Severe asthma exacerbations were defined according to GINA guidelines during p1 and p2. During p3, we defined severe asthma deterioration as the onset of breathlessness and wheezing requiring systemic corticosteroids and inhaled beta-2-agonist. Results We found no significant difference between asthmatics and non-asthmatics in terms of severity (length of stay, maximal oxygen flow needed, non-invasive ventilation requirement and ICU transfer). 52.2% of the asthmatic patients were Gina 1. One patient had a severe exacerbation during p1, two patients during p2, and five patients were treated with systemic corticosteroids and inhaled beta-2-agonist during p3. Conclusion Our results demonstrate that asthmatic patients appeared not to be at risk for severe SARS-CoV-2 pneumonia. Moreover, SARS-CoV-2 pneumonia did not induce severe asthma exacerbation., Highlights box: 1. What is already known about this topic? Asthmatic patients are rare in epidemiological studies of SARS-CoV-2 pneumonia. 2. What does this article add to our knowledge? Being asthmatic is not a risk factor for severe SARS-CoV-2. 3. How does this study impact current management guidelines? SARS-CoV-2 pneumonia may not induce severe asthma exacerbation.
Published: 2020

3. Entry Inhibitors: A Perspective for Prevention of Hepatitis C Virus Infection in Organ Transplantation

Author: Thomas F. Baumert, Che C. Colpitts, Raymond T. Chung, Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Gastrointestinal Division [Boston, MA, USA] (Liver Center - Department of Medicine), Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], and Interaction virus-hôte et maladies du foie
Subjects: 0301 basic medicine, medicine.medical_specialty, Hepatitis C virus, Treatment outcome, Context (language use), Hepacivirus, Disease, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Biology, medicine.disease_cause, Antiviral Agents, Article, Organ transplantation, 03 medical and health sciences, 0302 clinical medicine, Clinical investigation, medicine, Humans, entry inhibitors, Clinical Trials as Topic, organ transplantation, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Virus Internalization, Hepatitis C, Tissue Donors, 3. Good health, Transplantation, Treatment Outcome, 030104 developmental biology, Infectious Diseases, Viral replication, Immunology, 030211 gastroenterology & hepatology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Entry inhibitors are emerging as an attractive class of therapeutics for hepatitis C virus (HCV) infection. Entry inhibitors target either virion-associated factors or cellular factors necessary for infection. By blocking entry into cells, entry inhibitors prevent both the establishment of persistent reservoirs and the emergence of resistant variants during viral replication. Furthermore, entry inhibitors protect naïve cells from virus-induced alterations. Combining entry inhibitors with direct acting antivirals (DAAs) may therefore improve treatment outcomes, particularly in the context of organ transplantation. The role of DAAs in transplantation is still under clinical investigation, yet carries the risk of recipient infection and HCV-induced disease, since DAAs act only after infection is established. Using entry inhibitors to block infection in transplanted individuals will likely improve patient outcomes during organ transplantation. This may also open perspectives for transplant of organs from HCV-positive donors to HCV-negative recipients to alleviate the medical burden of organ shortage.
Published: 2017

4. Resistance to integrase inhibitors: a national study in HIV-1-infected treatment-naive and -experienced patients

Author: Constance Delaugerre, Virginie Ferré, Anne Maillard, Vincent Calvez, Audrey Mirand, Anne-Geneviève Marcelin, Corinne Amiel, Julia Dina, Coralie Pallier, Hélène Le Guillou-Guillemette, Stéphanie Raymond, D. B. Fofana, Thomas Mourez, Hélène Jeulin, Samira Fafi-Kremer, Brigitte Montes, Pantxika Bellecave, Sophie Vallet, Thuy Van Nguyen, Diane Descamps, Catherine Roussel, Maxime Grude, Mary-Anne Trabaud, Charlotte Charpentier, Laurence Bocket, Philippe Flandre, Laura Le Guen, Anne Signori-Schmuck, Epidémiologie, stratégies thérapeutiques et virologie cliniques dans l'infection à VIH, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Laboratoire Bordelais de Recherche en Informatique (LaBRI), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB), Microbiologie cellulaire et moléculaire et pathogénicité (MCMP), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Nantes (CHU Nantes), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Toulouse [Toulouse], Laboratoire Microorganismes : Génome et Environnement (LMGE), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), CIC CHU ( Lille)/inserm, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Laboratoire de Virologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Simulation et Traitement de l'information pour l'Exploitation des systèmes de Production (EDF R&D STEP), EDF R&D (EDF R&D), EDF (EDF)-EDF (EDF), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Groupe de Recherche sur l'Adaptation Microbienne (GRAM 2.0), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Laboratoire de virologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Amiens-Picardie, Service de Virologie [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Laboratoire Universitaire de Biodiversité et Ecologie Microbienne (LUBEM), Université de Brest (UBO), Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Virologie [Rennes] = Virology [Rennes], CHU Pontchaillou [Rennes], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Microbiologie Fondamentale et Pathogénicité (MFP), Service de virologie et unité de surveillance biologique [Bordeaux], CHU Bordeaux [Bordeaux], Hôpital Paul Brousse, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Virologie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Clermont-Ferrand, CHU Lille, CHU Saint-Antoine [AP-HP], Laboratoire de Virologie [CHU Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Hôpital Saint Eloi (CHRU Montpellier), Service de Virologie [CHRU Nancy], CHU Strasbourg, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Centre Hospitalier Universitaire [Grenoble] (CHU), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Université de Caen Normandie (UNICAEN), Service de Virologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)-Université Sorbonne Paris Nord, Hôpital Paul Brousse-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Virologie [Toulouse], CHU Saint-Eloi, Mzembaba, Sandy, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, 0301 basic medicine, MESH: Sequence Analysis, DNA, MESH: Treatment Failure, Aucun, Integrase inhibitor, HIV Infections, Drug resistance, MESH: HIV Seropositivity / drug therapy, MESH: Genotype, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, MESH: Risk Factors, HIV Seropositivity, Pharmacology (medical), Treatment Failure, 030212 general & internal medicine, ComputingMilieux_MISCELLANEOUS, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: Middle Aged, biology, Elvitegravir, Middle Aged, Viral Load, 3. Good health, Integrase, MESH: HIV-1 / genetics, Infectious Diseases, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Dolutegravir, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Female, Viral load, medicine.drug, Adult, Microbiology (medical), medicine.medical_specialty, MESH: Mutation, Genotype, MESH: HIV Integrase Inhibitors / therapeutic use, 030106 microbiology, MESH: HIV Infections / drug therapy, MESH: Drug Resistance, Multiple, Viral / genetics, MESH: HIV-1 / drug effects, 03 medical and health sciences, Drug Resistance, Multiple, Viral, Internal medicine, medicine, Humans, HIV Integrase Inhibitors, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Pharmacology, MESH: Viral Load / drug effects, MESH: Humans, business.industry, MESH: Adult, Sequence Analysis, DNA, Raltegravir, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, MESH: Male, Regimen, chemistry, Mutation, HIV-1, biology.protein, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, business, MESH: Female
Abstract: International audience; Objectives: To describe integrase strand transfer inhibitor (INSTI) resistance profiles and factors associated with resistance in antiretroviral-naive and -experienced patients failing an INSTI-based regimen in clinical practice.Methods: Data were collected from patients failing an INSTI-containing regimen in a multicentre French study between 2014 and 2017. Failure was defined as two consecutive plasma viral loads (VL) >50 copies/mL. Reverse transcriptase, protease and integrase coding regions were sequenced at baseline and failure. INSTI resistance-associated mutations (RAMs) included in the Agence Nationale de Recherches sur le SIDA genotypic algorithm were investigated.Results: Among the 674 patients, 359 were failing on raltegravir, 154 on elvitegravir and 161 on dolutegravir therapy. Overall, 90% were experienced patients and 389 (58%) patients showed no INSTI RAMs at failure. The strongest factors associated with emergence of at least one INSTI mutation were high VL at failure (OR = 1.2 per 1 log10 copies/mL increase) and low genotypic sensitivity score (GSS) (OR = 0.08 for GSS ≥3 versus GSS = 0-0.5). Patients failing dolutegravir also had significantly fewer INSTI RAMs at failure than patients failing raltegravir (OR = 0.57, P = 0.02) or elvitegravir (OR = 0.45, P = 0.005). Among the 68 patients failing a first-line regimen, 11/41 (27%) patients on raltegravir, 7/18 (39%) on elvitegravir and 0/9 on dolutegravir had viruses with emergent INSTI RAMs at failure.Conclusions: These results confirmed the robustness of dolutegravir regarding resistance selection in integrase in the case of virological failure in routine clinical care.
Published: 2019

5. Status of Direct-Acting Antiviral Therapy for Hepatitis C Virus Infection and Remaining Challenges

Author: Thomas Berg, David R. Nelson, Joseph K. Lim, Thomas F. Baumert, Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle Hépato-digestif [Strasbourg] (HUS - Nouvel Hôpital Civil), Les Hôpitaux Universitaires de Strasbourg (HUS), Yale School of Medicine [New Haven, Connecticut] (YSM), University of Florida [Gainesville] (UF), ANR-10-LABX-0028,HepSys,Functional genomics of viral hepatitis and liver disease(2010), European Project: 671231,H2020,ERC-2014-ADG,HEPCIR(2016), European Project: 667273,H2020,H2020-PHC-2015-two-stage,HEP-CAR(2016), and Yale University School of Medicine
Subjects: 0301 basic medicine, Sustained Virologic Response, Hepatitis C virus, Resistance, Aucun, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, medicine.disease_cause, Bioinformatics, Treatment failure, 03 medical and health sciences, Liver disease, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, medicine, Humans, Treatment Failure, Direct-Acting Antivirals, Hepatology, business.industry, Gastroenterology, Antiviral therapy, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Hepatitis C, medicine.disease, 3. Good health, Chronic infection, 030104 developmental biology, Hepatocellular carcinoma, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, 030211 gastroenterology & hepatology, business, Direct acting
Abstract: PMC6446912; Chronic infection with hepatitis C virus is a major cause of liver disease and hepatocellular carcinoma worldwide. After the discovery of hepatitis C virus 3 decades ago, the identification of the structure of the viral proteins, combined with high-throughput replicon models, enabled the discovery and development of direct-acting antivirals. These agents have revolutionized patient care, with cure rates of more than 90%. We review the status of direct-acting antiviral therapies for hepatitis C virus infection and discuss remaining challenges. We highlight licensed compounds, discuss the potential to shorten therapy even further, and review different options for treatment failure and resistance. We also provide an overview of clinical experience with generic agents and evidence for their efficacy. Finally, we discuss the need for new drugs and outline promising targets for future therapies.
Published: 2019

6. Functional microRNA screen uncovers O-linked N-acetylglucosamine transferase as a host factor modulating hepatitis C virus morphogenesis and infectivity

Author: Hervé Lerat, Jean-Christophe Meunier, Sarah C. Durand, Thomas Baumert, Mirjam B. Zeisel, Laurent Brino, Amélie Weiss, Frank Jühling, Béatrice Chane-Woon-Ming, Catherine Fauvelle, Sophie Pernot, Marion Mercey, Anne Bull, Sébastien Pfeffer, Katharina Herzog, Wolfgang Raffelsberger, Simonetta Bandiera, Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH - U1259 Inserm - CHRU Tours ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Interactions Virus-Hôte et Maladies Hépatiques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Virologie, Interaction virus-hôte et maladies du foie, MATHELIN, Sandra, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Maladies Virales et Hépatiques, inserm U1110, University of Leipzig (Bioinformatics Group), Universität Leipzig [Leipzig], Virus, pseudo-virus: Morphogénèse et Antigénicité, Université de Tours-EA3856, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut für Physik and CINSaT, Universität Kassel, and Universität Kassel [Kassel]
Subjects: [SDV]Life Sciences [q-bio], Cell, molecular mechanisms, Hepacivirus, medicine.disease_cause, Liver disease, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Gene expression, Sciences du Vivant [q-bio]/Biologie cellulaire, Morphogenesis, ComputingMilieux_MISCELLANEOUS, Host factor, Infectivity, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 0303 health sciences, Virulence, Gastroenterology, virus diseases, 3. Good health, Cell biology, Up-Regulation, medicine.anatomical_structure, Gene Knockdown Techniques, Host-Pathogen Interactions, Hcv, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], 030211 gastroenterology & hepatology, Hepatitis C virus, Biology, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, N-Acetylglucosaminyltransferases, Sciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire, Article, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], microRNA, medicine, hepatocyte, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Life Cycle Stages, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Hepatitis C, Chronic, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, digestive system diseases, MicroRNAs, Gene Expression Regulation, Hepatocytes, hepatitis C, Genome-Wide Association Study
Abstract: ObjectiveInfection of human hepatocytes by the hepatitis C virus (HCV) is a multistep process involving both viral and host factors. microRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression. Given that miRNAs were indicated to regulate between 30% and 75% of all human genes, we aimed to investigate the functional and regulatory role of miRNAs for the HCV life cycle.DesignTo systematically reveal human miRNAs affecting the HCV life cycle, we performed a two-step functional high-throughput miRNA mimic screen in Huh7.5.1 cells infected with recombinant cell culture-derived HCV. miRNA targeting was then assessed using a combination of computational and functional approaches.ResultsWe uncovered miR-501-3p and miR-619-3p as novel modulators of HCV assembly/release. We discovered that these miRNAs regulate O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) protein expression and identified OGT and O-GlcNAcylation as regulators of HCV morphogenesis and infectivity. Furthermore, increased OGT expression in patient-derived liver tissue was associated with HCV-induced liver disease and cancer.ConclusionmiR-501-3p and miR-619-3p and their target OGT are previously undiscovered regulatory host factors for HCV assembly and infectivity. In addition to its effect on HCV morphogenesis, OGT may play a role in HCV-induced liver disease and hepatocarcinogenesis.
Published: 2019

7. Claudins in viral infection: from entry to spread

Author: Thomas F. Baumert, Che C. Colpitts, Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Interaction virus-hôte et maladies du foie, and daulny, anne
Subjects: 0301 basic medicine, Physiology, viruses, Viral pathogenesis, Clinical Biochemistry, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Dengue virus, Biology, medicine.disease_cause, Antiviral Agents, Article, Tight Junctions, 03 medical and health sciences, 0302 clinical medicine, Physiology (medical), Cell polarity, medicine, Animals, Humans, Claudin, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Tight Junction Proteins, Innate immune system, Tight junction, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Virology, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, Cell biology, 030104 developmental biology, Virus Diseases, Paracellular transport, Claudins, Signal transduction, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract: Tight junctions are critically important for many physiological functions, including the maintenance of cell polarity, regulation of paracellular permeability, and involvement in signal transduction pathways to regulate integral cellular processes. Furthermore, tight junctions enable epithelial cells to form physical barriers, which act as an innate immune mechanism that can impede viral infection. Viruses, in turn, have evolved mechanisms to exploit tight junction proteins to gain access to cells or spread through tissues in an infected host. Claudin family proteins are integral components of tight junctions and are thought to play crucial roles in regulating their permeability. Claudins have been implicated in the infection process of several medically important human pathogens, including hepatitis C virus, dengue virus, West Nile virus, and human immunodeficiency virus, among others. In this review, we summarize the role of claudins in viral infections and discuss their potential as novel antiviral targets. A better understanding of claudins during viral infection may provide insight into physiological roles of claudins and uncover novel therapeutic antiviral strategies.
Published: 2016

8. Hepatitis C virus vaccine candidates inducing protective neutralizing antibodies

Author: Steven K. H. Foung, Catherine Fauvelle, Thomas F. Baumert, Brian G. Pierce, Che C. Colpitts, Zhen-Yong Keck, Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Pathology [Stanford], Stanford Medicine, Stanford University-Stanford University, Institute for Bioscience and Biotechnology Research [Rockville, MD, États-Unis] (IBBR), University of Maryland [College Park], University of Maryland System-University of Maryland System, Interaction virus-hôte et maladies du foie, and R21 AI126582
Subjects: 0301 basic medicine, Hepatitis C virus, Immunology, Hepacivirus, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Biology, medicine.disease_cause, Article, 03 medical and health sciences, Immune system, Viral envelope, Immunity, vaccine, Drug Discovery, medicine, Global health, antibodies, Animals, Humans, Pharmacology, chemistry.chemical_classification, Viral Vaccines, Hepatitis C, Hepatitis C Antibodies, Hepatitis C, Chronic, medicine.disease, immunity, Antibodies, Neutralizing, Virology, 3. Good health, 030104 developmental biology, chemistry, biology.protein, Molecular Medicine, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, Antibody, Glycoprotein
Abstract: Introduction: With more than 150 million chronically infected people, hepatitis C virus (HCV) remains a substantial global health burden. Direct-acting antivirals have dramatically improved viral cure. However, limited access to therapy, late stage detection of infection and re-infection following cure illustrate the need for a vaccine for global control of infection. Vaccines with induction of neutralizing antibodies (nAbs) have been shown to protect successfully against infections by multiple viruses and are currently developed for HCV.Areas covered: Here we review the progress towards the development of vaccines aiming to confer protection against chronic HCV infection by inducing broadly nAbs. The understanding or viral immune evasion in infected patients, the development of novel model systems and the recent structural characterization of viral envelope glycoprotein E2 has markedly advanced our understanding of the molecular mechanisms of virus neutralization with the concomitant development of several vaccine candidates.Expert commentary: While HCV vaccine development remains challenged by the high viral diversity and immune evasion, marked progress in HCV research has advanced vaccine design. Several vaccine candidates have shown robust induction of nAbs in animal models and humans. Randomized clinical trials are the next step to assess their clinical efficacy for protection against chronic infection.
Published: 2016

9. Sequence Variation in Amplification Target Genes and Standards Influences Interlaboratory Comparison of BK Virus DNA Load Measurement

Author: Pilar Domingo-Calap, Bruno MOULIN, Valerie Giordanengo, Seiamak Bahram, Véronique Avettand-Fenoel, Sébastien Hantz, Samira Fafi-Kremer, Jerome LeGoff, ALEXANDRA DUCANCELLE, Bruno POZZETTO, Sophie Caillard, ERIC SOULIER, Peggy Perrin, Sylvie Pillet, Morgane Solis, Astrid VABRET, Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Les Hôpitaux Universitaires de Strasbourg (HUS), French BKV Study Group, Laboratoire de Virologie [Hôpitaux universitaires de Strasbourg], Immunorhumathologie moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM), Virulence bactérienne précoce, Université de Strasbourg (EA7290), Unit for Virus Host-Cell Interactions [Grenoble] (UVHCI), Université Joseph Fourier - Grenoble 1 (UJF)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Centre National de la Recherche Scientifique (CNRS), CHU Strasbourg, Service de Néphrologie et Transplantation, Interaction virus-hôte et maladies du foie, Laboratoire Microorganismes : Génome et Environnement - Clermont Auvergne (LMGE), Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Virulence Bactérienne Précoce : fonctions cellulaires et contrôle de l'infection aigüe et subaigüe, Université de Strasbourg (UNISTRA), Centre National de la Recherche Scientifique (CNRS)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Université Joseph Fourier - Grenoble 1 (UJF), Laboratoire Microorganismes : Génome et Environnement (LMGE), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), and BRICHEUX, Genevieve
Subjects: Microbiology (medical), Laboratory Proficiency Testing, viruses, 030230 surgery, Biology, medicine.disease_cause, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Sensitivity and Specificity, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, isolation & purification, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Virology, Genetic variation, Genotype, medicine, Humans, Sequence variation, methods, standards, Gene, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Genetics, Sciences du Vivant [q-bio]/Ingénierie biomédicale, Polyomavirus Infections, 0303 health sciences, diagnosis, virology, 030306 microbiology, genetics, Genetic Variation, virus diseases, Viral Load, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, DNA extraction, Hospitals, 3. Good health, BK virus, BK Virus, DNA, Viral, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, France, Primer (molecular biology), Viral load
Abstract: International guidelines define a BK virus (BKV) load of ≥4 log 10 copies/ml as presumptive of BKV-associated nephropathy (BKVN) and a cutoff for therapeutic intervention. To investigate whether BKV DNA loads (BKVL) are comparable between laboratories, 2 panels of 15 and 8 clinical specimens (urine, whole blood, and plasma) harboring different BKV genotypes were distributed to 20 and 27 French hospital centers in 2013 and 2014, respectively. Although 68% of the reported results fell within the acceptable range of the expected result ±0.5 log 10 , the interlaboratory variation ranged from 1.32 to 5.55 log 10 . Polymorphisms specific to BKV genotypes II and IV, namely, the number and position of mutations in amplification target genes and/or deletion in standards, arose as major sources of interlaboratory disagreements. The diversity of DNA purification methods also contributed to the interlaboratory variability, in particular for urine samples. Our data strongly suggest that (i) commercial external quality controls for BKVL assessment should include all major BKV genotypes to allow a correct evaluation of BKV assays, and (ii) the BKV sequence of commercial standards should be provided to users to verify the absence of mismatches with the primers and probes of their BKV assays. Finally, the optimization of primer and probe design and standardization of DNA extraction methods may substantially decrease interlaboratory variability and allow interinstitutional studies to define a universal cutoff for presumptive BKVN and, ultimately, ensure adequate patient care.
Published: 2015

10. SCARB1 variants and HCV infection: Host susceptibility is lost in translation

Author: Che C. Colpitts, Thomas F. Baumert, Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Interaction virus-hôte et maladies du foie, and daulny, anne
Subjects: 0301 basic medicine, Hepacivirus, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Virus Replication, 03 medical and health sciences, medicine, Humans, Scavenger receptor, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Hepatology, biology, Host (biology), [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Translation (biology), Hepatitis C, Scavenger Receptors, Class B, Viral Load, biology.organism_classification, medicine.disease, Virology, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, SCARB1, 030104 developmental biology, Viral replication, Viral load, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: n/a
Published: 2017

11. SMAD About Hepatitis C Virus Cell Entry and Liver Disease

Author: Che C. Colpitts, Thomas F. Baumert, Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Interaction virus-hôte et maladies du foie
Subjects: 0301 basic medicine, Bone Morphogenetic Protein 6, Smad6 Protein, Bone Morphogenetic Protein 7, Lipoproteins, Hepatitis C virus, Hepacivirus, SMAD, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Transfection, medicine.disease_cause, Article, Smad7 Protein, 03 medical and health sciences, Liver disease, Text mining, medicine, Humans, RNA, Messenger, RNA, Small Interfering, Cell entry, Hepatology, business.industry, NF-kappa B, Gastroenterology, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Hep G2 Cells, Hepatitis C, Chronic, Virus Internalization, medicine.disease, Virology, Up-Regulation, Cholesterol, 030104 developmental biology, Receptors, LDL, Gene Knockdown Techniques, Hepatocytes, RNA, Viral, Syndecan-1, business, Heparan Sulfate Proteoglycans, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Signal Transduction
Abstract: The signaling molecule and transcriptional regulator SMAD6, which inhibits the transforming growth factor β signaling pathway, is required for infection of hepatocytes by hepatitis C virus (HCV). We investigated the mechanisms by which SMAD6 and another inhibitory SMAD (SMAD7) promote HCV infection in human hepatoma cells and hepatocytes.We infected Huh7 and Huh7.5.1 cells and primary human hepatocytes with Japanese fulminant hepatitis-1 (JFH1) HCV cell culture system (HCVcc). We then measured HCV binding, intracellular levels of HCV RNA, and expression of target genes. We examined HCV entry in HepG2/microRNA (miR) 122/CD81 cells, which support entry and replication of HCV, were transfected these cells with small interfering RNAs targeting inhibitory SMADs to analyze gene expression profiles. Uptake of labeled low-density lipoprotein (LDL) and cholesterol was measured. Cell surface proteins were quantified by flow cytometry. We obtained liver biopsy samples from 69 patients with chronic HCV infection and 19 uninfected individuals (controls) and measured levels of syndecan 1 (SDC1), SMAD7, and SMAD6 messenger RNAs (mRNAs).Small interfering RNA knockdown of SMAD6 blocked the binding and infection of hepatoma cell lines and primary human hepatocytes by HCV, whereas SMAD6 overexpression increased HCV infection. We found levels of mRNAs encoding heparan sulfate proteoglycans (HSPGs), particularly SDC1 mRNA, and cell surface levels of heparan sulfate to be reduced in cells after SMAD6 knockdown. SMAD6 knockdown also reduced transcription of genes encoding lipoprotein and cholesterol uptake receptors, including the LDL receptor (LDLR), the very LDLR, and the scavenger receptor class B member 1 in hepatocytes; knockdown of SMAD6 also inhibited cell uptake of cholesterol and lipoprotein. Overexpression of SMAD6 increased the expression of these genes. Similar effects were observed with knockdown and overexpression of SMAD7. In addition, HCV infection of cells increased the expression of SMAD6, which required the activity of nuclear factor-κB, but not transforming growth factor β. Liver tissues from patients with chronic HCV infection had significantly higher levels of SMAD6, SMAD7, and HSPG mRNAs than controls.In studies of hepatoma cell lines and primary human hepatocytes, we found that infection with HCV leads to activation of nuclear factor-κB, resulting in increased expression of SMAD6 and SMAD7. Up-regulation of SMAD6 and SMAD7 induces the expression of HSPGs, such as SDC1, as well as LDLR, very LDLR, and the scavenger receptor class B member 1, which promote HCV entry and propagation, as well as cellular uptake of cholesterol and lipoprotein.
Published: 2017

12. Stable prevalence of transmitted drug resistance mutations and increased circulation of non-B subtypes in antiretroviral-naive chronically HIV-infected patients in 2015/2016 in France

Author: Gilles Peytavin, Mary-Anne Trabaud, Anne Signori-Schmuck, Charlotte Charpentier, Marc Wirden, Cécile Henquell, Laurence Bocket, Catherine Delamare, Samira Fafi-Kremer, Jacques Izopet, Chakib Allaoui, Georges Dos Santos, A. Beby-Defaux, Benoit Visseaux, Virginie Ferré, Coralie Pallier, Diane Descamps, Stéphanie Marque-Juillet, Lambert Assoumou, Magali Bouvier-Alias, Sophie Vallet, Alexis de Rougemont, Hélène Le Guillou-Guillemette, Vincent Calvez, Stéphanie Raymond, Corinne Amiel, Honorine Fenaux, Anne De Monte, Francis Barin, Anne Krivine, Véronique Avettand-Fenoel, Annick Allardet-Servent, Jean-Christophe Plantier, Rachid Ait-Namane, Laurence Morand-Joubert, Marie-Laure Chaix, Camille Tumiotto, Maxime Grude, Anne Maillard, Laurence Courdavault, Brigitte Montes, Epidémiologie, stratégies thérapeutiques et virologie cliniques dans l'infection à VIH, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC CHU ( Lille)/inserm, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Bordelais de Recherche en Informatique (LaBRI), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB), Service de Virologie [CHU Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Hôpital Avicenne [AP-HP], CHU Clermont-Ferrand, Service de Virologie [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU de la Martinique [Fort de France], Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Nice [Cimiez], Hôpital Cimiez [Nice] (CHU), Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Virologie [Rennes] = Virology [Rennes], CHU Pontchaillou [Rennes], Services des Maladies Infectieuses et Tropicales [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Bordeaux [Bordeaux], Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier de Versailles André Mignot (CHV), Centre Hospitalier Victor Dupouy, Laboratoire Universitaire de Biodiversité et Ecologie Microbienne (LUBEM), Université de Brest (UBO), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Procédés Alimentaires et Microbiologiques [Dijon] (PAM), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Service de Virologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Université Sorbonne Paris Cité (USPC), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Groupe de Recherche sur l'Adaptation Microbienne (GRAM 2.0), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Laboratoire de virologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Laboratoire de Virologie [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université de Caen Normandie (UNICAEN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Mzembaba, Sandy, Epidémiologie, Systèmes d'Information, Modélisation, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Virologie [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Paul Brousse, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Service de Virologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Service de Virologie Médicale et Moléculaire [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], Laboratoire de Virologie-Immunologie [Fort de France, Martinique] (EA 4537), Centre Hospitalier Universitaire de Martinique [Fort-de-France, Martinique], CHU Henri Mondor, Centre Hospitalier Universitaire [Grenoble] (CHU), Laboratoire de Virologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Sorbonne Université (SU), Service de virologie et unité de surveillance biologique [Bordeaux], CHU Strasbourg, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre hospitalier Argenteuil (CH Argenteuil), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université Paris Descartes, Sorbonne Paris Cité, Groupe de Recherche sur les Antimicrobiens et les Micro-Organismes (GRAM 1.0), Normandie Université (NU)-Normandie Université (NU), Pathologie cellulaire : aspects moléculaires et viraux / Pathologie et Virologie Moléculaire, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), and ANRS – France REcherche Nord&Sud Sida-hiv Hépatites
Subjects: 0301 basic medicine, Male, MESH: CD4 Lymphocyte Count, [SDV]Life Sciences [q-bio], Integrase inhibitor, hiv, HIV Infections, Drug resistance, MESH: HIV-1 / genetics, MESH: Genotype, MESH: HIV Infections / epidemiology, 0302 clinical medicine, Genotype, Blood plasma, HIV Seropositivity, rna-directed dna polymerase, Prevalence, rna, Pharmacology (medical), 030212 general & internal medicine, MESH: Chronic Disease / epidemiology, ComputingMilieux_MISCELLANEOUS, cd4 count determination procedure, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, anti-retroviral agents, MESH: France / epidemiology, Antiinfective agent, MESH: Middle Aged, Incidence (epidemiology), Middle Aged, MESH: Drug Resistance, Viral / genetics, 3. Good health, endopeptidases, [SDV] Life Sciences [q-bio], integrase inhibitors, Infectious Diseases, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, RNA, Viral, MESH: RNA, Viral / blood, Female, France, MESH: HIV Seropositivity / epidemiology, Microbiology (medical), Adult, medicine.medical_specialty, peptide hydrolases, MESH: Mutation, Anti-HIV Agents, 030106 microbiology, MESH: HIV Infections / drug therapy, MESH: HIV-1 / classification, MESH: HIV-1 / drug effects, Virus, MESH: HIV Infections / transmission, 03 medical and health sciences, Pharmacotherapy, Internal medicine, Drug Resistance, Viral, medicine, Humans, viruses, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, plasma, safe sex, MESH: Prevalence, Pharmacology, drug resistance, MESH: Humans, business.industry, MESH: Adult, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, MESH: Male, CD4 Lymphocyte Count, MESH: Anti-HIV Agents / therapeutic use, Chronic Disease, Mutation, HIV-1, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, business, MESH: Female
Abstract: International audience; Objectives: We estimated the prevalence of transmitted-drug-resistance-associated mutations (TDRAMs) in antiretroviral-naive chronically HIV-1-infected patients.Patients and methods: TDRAMs were sought in samples from 660 diagnosed HIV-1-infected individuals in 2015/2016 in 33 HIV clinical centres. Weighted analyses, considering the number of patients followed in each centre, were used to derive representative estimates of the percentage of individuals with TDRAMs. Results were compared with those of the 2010/2011 survey (n = 661) using the same methodology.Results: At inclusion, median CD4 cell counts and plasma HIV-1 RNA were 394 and 350/mm3 (P = 0.056) and 4.6 and 4.6 log10 copies/mL (P = 0.360) in the 2010/2011 survey and the 2015/2016 survey, respectively. The frequency of non-B subtypes increased from 42.9% in 2010/2011 to 54.8% in 2015/2016 (P < 0.001), including 23.4% and 30.6% of CRF02_AG (P = 0.004). The prevalence of virus with protease or reverse-transcriptase TDRAMs was 9.0% (95% CI = 6.8-11.2) in 2010/2011 and 10.8% (95% CI = 8.4-13.2) in 2015/2016 (P = 0.269). No significant increase was observed in integrase inhibitor TDRAMs (6.7% versus 9.2%, P = 0.146). Multivariable analysis showed that men infected with the B subtype were the group with the highest risk of being infected with a resistant virus compared with others (adjusted OR = 2.2, 95% CI = 1.3-3.9).Conclusions: In France in 2015/2016, the overall prevalence of TDRAMs was 10.8% and stable compared with 9.0% in the 2010/2011 survey. Non-B subtypes dramatically increased after 2010. Men infected with B subtype were the group with the highest risk of being infected with a resistant virus, highlighting the need to re-emphasize safe sex messages.
Published: 2018

13. Emerging resistance mutations in PI-naive patients failing an atazanavir-based regimen (ANRS multicentre observational study)

Author: Lambert-Niclot, L, Grude, C, Chaix, L., Charpentier, L, Reigadas, C, Le Guillou-Guillemette, L, Rodallec, C, Maillard, Pascale, Dufayard, C, Mourez, C, Mirand, C, Guinard, L, Montes, S, Vallet, L, Marcelin, Marc, Descamps, L, Flandre, C, Delaugerre, L, Alloui, Chakib, Descamps, Diane, Charpentier, Charlotte, Visseaux, Benoit, Krivine, Anne, Bouviers-Alias, Ali, Pallier, Coralie, Soulié, Cathia, Wirden, Marc, Marcelin, Anne, Calvez, Vincent, Morand, Laurence, Lambert-Niclot, Sidonie, Fofana, Djeneba, Mahjoub, Nadia, Delaugerre, Constance, Chaix, Marie, Amiel, Corinne, Schneider, Veronique, Roussel, Catherine, Le Guillou-Guillemette, Hélène, Courdavault, Laurence, Reigadas, Sandrine, Recordon-Pinson, Patricia, Fleury, Hervé, Vallet, Sophie, Dina, Julia, Vabret, Astrid, Mirand, Audrey, Henquell, Cécile, Auvray, Christelle, de Rougemont, Alexis, Giraudon, Helene, Si-Mohammed, Ali, Mathez, Dominique, Signori-Schmuck, Anne, Morand, Patrice, Bocket, Laurence, Trabaud, Anne, Montes, Brigitte, Le Guen, Laura, Rodallec, Audrey, Ferré, Virginie, Jeulin, Hélène, SCHVOERER, Evelyne, Dufayard, Jacqueline, Allardet-Servent, Annick, carles, Marie, Guinard, Jérôme, Guigon, Aurélie, Giraudeau, Genevieve, Beby-Defaux, Agnès, Maillard, Anne, Plantier, Jean Christophe, Leoz, Marie, Mourez, Thomas, Bourlet, Thomas, Fafi-Kremer, Samira, Chiabrando, Julie, Raymond, Stéphanie, Izopet, Jacques, Barin, Francis, Marque-Juillet, Stéphanie, Yerly, Sabine, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Pontchaillou, Centre Hospitalier Universitaire de Nice (CHU Nice), CHU Rouen, Normandie Université (NU), CHU Clermont-Ferrand, Centre Hospitalier Régional d'Orléans (CHRO), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire Bordelais de Recherche en Informatique (LaBRI), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Service de virologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Epidémiologie, stratégies thérapeutiques et virologie cliniques dans l'infection à VIH, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Mathématiques et Applications - ENS Paris (DMA), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Département d'Astrophysique, de physique des Particules, de physique Nucléaire et de l'Instrumentation Associée (DAPNIA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire de Virologie [CHU Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Génétique et Ecologie des Virus, Génétique des Virus et Pathogénèse des Maladies Virales, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), UFR des Sciences de Santé (Université de Bourgogne), Université de Bourgogne (UB), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Centre Hospitalier Victor Dupouy, Microbiologie cellulaire et moléculaire et pathogénicité (MCMP), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), CHU Bordeaux [Bordeaux], Laboratoire Universitaire de Biodiversité et Ecologie Microbienne (LUBEM), Université de Brest (UBO), Laboratoire de Virologie Humaine et Moléculaire [Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Groupe de Recherche sur l'Adaptation Microbienne (GRAM 2.0), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université de Caen Normandie (UNICAEN), Laboratoire Microorganismes : Génome et Environnement (LMGE), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Laboratoire de sérologie-virologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hôpital Raymond Poincaré [AP-HP], Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Département de virologie [Grenoble], Centre Hospitalier Universitaire [Grenoble] (CHU), Service de Virologie [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Epidémiologie, Démographie et Sciences Sociales: santé reproductive, sexualité et infection à VIH (Inserm U569), Epidémiologie, sciences sociales, santé publique (IFR 69), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut national d'études démographiques (INED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Chimie Physique et Microbiologie pour les Matériaux et l'Environnement (LCPME), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Observatoire des Programmes Communautaires de Développement Rural (US ODR), Institut National de la Recherche Agronomique (INRA), Institut Pasteur de Nouvelle-Calédonie, Réseau International des Instituts Pasteur (RIIP), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Ecophysiologie Végétale, Agronomie et Nutritions (EVA), Institut National de la Recherche Agronomique (INRA)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Groupe Immunité des Muqueuses et Agents Pathogènes (GIMAP), Université Jean Monnet [Saint-Étienne] (UJM), Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Claude de Préval (ICP), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université de Tours (UT), Centre Hospitalier de Versailles André Mignot (CHV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université de Bordeaux (UB)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Centre National de la Recherche Scientifique (CNRS), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), École normale supérieure - Paris (ENS-PSL), Microbiologie Fondamentale et Pathogénicité (MFP), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Recherche Agronomique (INRA), Université Jean Monnet - Saint-Étienne (UJM), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Université de Tours, Service de Virologie [CHU Pitié-Salpêtrière], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Lycée agricole La Touche, Hôpital Bichat - Claude Bernard, Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Université Sciences et Technologies - Bordeaux 1-Université Bordeaux Segalen - Bordeaux 2, Memo-Flu-ARDS Study Group, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], École normale supérieure - Paris (ENS Paris)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), CHU Tenon [APHP], Hôpital d'Argenteuil, Laboratoire Microorganismes : Génome et Environnement - Clermont Auvergne (LMGE), Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), AP-HP Hôpital Raymond Poincaré [Garches], Unit for Virus Host-Cell Interactions [Grenoble] (UVHCI), Université Joseph Fourier - Grenoble 1 (UJF)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de virologie moléculaire et structurale, CHU Grenoble, Laboratoire de virologie [CHU Lille], Université Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut national d'études démographiques (INED), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Centre national de référence du VIH INSERM U966, Centre Hospitalier de Versailles (CHV), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: 0301 basic medicine, Microbiology (medical), Adult, Male, medicine.medical_specialty, 030106 microbiology, Atazanavir Sulfate, HIV Infections, Emtricitabine, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Abacavir, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Internal medicine, Drug Resistance, Viral, medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, Treatment Failure, Tenofovir, ComputingMilieux_MISCELLANEOUS, Retrospective Studies, Pharmacology, business.industry, virus diseases, Lamivudine, HIV Protease Inhibitors, Middle Aged, Viral Load, Resistance mutation, Dideoxynucleosides, 3. Good health, Atazanavir, Regimen, Drug Combinations, Infectious Diseases, Mutation, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, HIV-1, Ritonavir, business, Viral load, medicine.drug
Abstract: Background Atazanavir is a PI widely used as a third agent in combination ART. We aimed to determine the prevalence and the patterns of resistance in PI-naive patients failing on an atazanavir-based regimen. Methods We analysed patients failing on an atazanavir-containing regimen used as a first line of PI therapy. We compared the sequences of reverse transcriptase and protease before the introduction of atazanavir and at failure [two consecutive viral loads (VLs) >50 copies/mL]. Resistance was defined according to the 2014 Agence Nationale de Recherche sur le SIDA et les Hepatites Virales (ANRS) algorithm. Results Among the 113 patients, atazanavir was used in the first regimen in 71 (62.8%) patients and in the first line of a PI-based regimen in 42 (37.2%). Atazanavir was boosted with ritonavir in 95 (84.1%) patients and combined with tenofovir/emtricitabine or lamivudine (n = 81) and abacavir/lamivudine or emtricitabine (n = 22). At failure, median VL was 3.05 log10 copies/mL and the median CD4+ T cell count was 436 cells/mm3. The median time on atazanavir was 21.2 months. At failure, viruses were considered resistant to atazanavir in four patients (3.5%) with the selection of the following major atazanavir-associated mutations: I50L (n = 1), I84V (n = 2) and N88S (n = 1). Other emergent PI mutations were L10V, G16E, K20I/R, L33F, M36I/L, M46I/L, G48V, F53L, I54L, D60E, I62V, A71T/V, V82I/T, L90M and I93L/M. Emergent NRTI substitutions were detected in 21 patients: M41L (n = 2), D67N (n = 3), K70R (n = 1), L74I/V (n = 3), M184V/I (n = 16), L210W (n = 1), T215Y/F (n = 3) and K219Q/E (n = 2). Conclusions Resistance to atazanavir is rare in patients failing the first line of an atazanavir-based regimen according to the ANRS. Emergent NRTI resistance-associated mutations were reported in 18% of patients.
Published: 2018

14. Impact of Human Immunodeficiency Virus Type 1 Minority Variants on the Virus Response to a Rilpivirine-Based First-line Regimen

Author: Raymond, E, Nicot, F., Morand-Joubert, A, Rodallec, D, Mourez, M, Beby-Defaux, D, Lambert-Niclot, P, Charpentier, E, Malvé, B., Le Guillou-Guillemette, A, Si-Mohamed, D, Avettand Fenoel, A, Roussel, A., Calvez, P, Saune, E, Rodriguez, M, Descamps, E, Izopet, E, Lagier, E, Roussel, C, Le Guillou-Guillemette, G, Alloui, A., Bettinger, D., Pallier, P, Fleury, Frédéric, Reigadas, R, Bellecave, P., Recordon-Pinson, P, Payan, P, Vallet, S., Vabret, A., Dina, D, Henquell, C., Mirand, A., Bouvier-Alias, A, de Rougemont, A, Dos Santos, D, Morand, P, Signori-Schmuck, A., Bocket, B, Rogez, R, Andre, A, Tardy, C, Trabaud, A, Tamalet, C., Delamare, D, Montes, B, SCHVOERER, Evelyne, Ferré, F., André-Garnier, E., Cottalorda, C, Guinard, G, Guiguon, A, Descamps, D., Brun-Vézinet, B, Charpentier, c, Visseaux, B, Peytavin, G., Krivine, A., Si-Mohamed, A, Avettand-Fenoel, Véronique, Marcelin, A, Calvez, C, Lambert-Niclot, L, Soulié, C., Wirden, M., Morand-Joubert, M, Delaugerre, D, Chaix, M, Amiel, A, Schneider, S., Giraudeau, G, Beby- Defaux, D, Brodard, B, Maillard, A., Plantier, P, Chaplain, C, Bourlet, B, Fafi-Kremer, F, Stoll-Keller, F., Schmit, P, Barth, B, Yerly, S, Poggi, P., Izopet, I, Raymond, R, Barin, B, Chaillon, A, Marque-Juillet, M, Roque-Afonso, A, Haïm-Boukobza, B, Flandre, P., Grudé, G, Assoumou, A, Costagliola, D, Allegre, A, Schmit, J, Chennebault, M, Bouchaud, B, Magy-Bertrand, B, Delfraissy, D, Dupon, D, Morlat, P, Neau, D, Ansart, A., Jaffuel, J, Verdon, R, Jacomet, C, Lévy, L, Dominguez, D, Chavanet, P., Piroth, P, Cabié, A., Leclercq, P, Ajana, A, Cheret, A, Weinbreck, P, Cotte, C, Poizot-Martin, P, Ravaud, R., Christian, B, Truchetet, F, Grandidier, G, Rey, R., May, M, Goehringer, G, Raffi, F., Dellamonica, D, Prazuck, P, Hocqueloux, L, Landman, R, Yazdanpanah, Y., Launay, L, WEISS, L, Viard, P, Katlama, C., Simon, A., Girard, G, Meynard, M, Molina, M, Pialoux, G, Hoen, B., Goeger-Sow, G, Lamaury, I, Beaucaire, G, Le Moal, G., Jaussaud, R., Rouger, C, Michelet, M., Borsa-Lebas, B, Caron, F, Khuong, A., Lucht, F., Rey, D., Calmy, A, Lafeuillade, A, Marchou, B, Delobel, D, Gras, G, Greder-Belan, A, Vittecoq, D, Teiche, E, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées, Laboratoire de virologie [CHU Toulouse], CHU Toulouse [Toulouse], Hôpital Paul Brousse, CHU Bordeaux [Bordeaux], Laboratoire de Virologie [Rennes] = Virology [Rennes], CHU Pontchaillou [Rennes], Hospices Civils de Lyon (HCL), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universiatire Hôtel-Dieu de Nantes (CHU Hôtel-Dieu), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Rouen, Centre Hospitalier Universitaire de Lille (CHU de Lille), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Hôpital Henri Mondor, CHU Pitié-Salpêtrière [AP-HP], Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM UMR-S 606, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, PRES Sorbonne Paris-Cité, and Université Paris Denis Diderot, Université Paris Diderot - Paris 7 (UPD7), Laboratoire de Virologie [AP-HP Hôpital Bichat-Claude-Bernard], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Nancy (CHU Nancy), CHU Clermont-Ferrand, Service de Virologie [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre de Référence des Maladies Auto-Inflammatoires et des Amyloses [CH Versailles] (CeRéMAIA - Hôpital André Mignot), Centre Hospitalier de Versailles André Mignot (CHV), Centre hospitalier universitaire de Grenoble (CHU de Grenoble), CHU Grenoble, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hôpital Necker, Centre Hospitalier Universitaire d'Amiens, Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP, Hôpital Henri-Mondor Albert-Chenevier, Service d'Immunologie Clinique et Maladies Infectieuses 94000 Créteil, France, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Agence Nationale de Recherches sur le SIDA et les hepatites virales (French National Agency for Research on AIDS and Viral Hepatitis, ANRS), Janssen-Cilag SAS, Erosion torrentielle neige et avalanches (UR ETGR (ETNA)), Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), Service de Virologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Laboratoire de Pharmacologie Médicale, Institut National de la Santé et de la Recherche Médicale (INSERM)-Faculté de Médecine/CHU, CHU Besançon, Université de Franche-Comté (UFC), Génétique et évolution des interactions hôtes-parasites, Département génétique, interactions et évolution des génomes [LBBE] (GINSENG), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Microbiologie cellulaire et moléculaire et pathogénicité (MCMP), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Laboratoire Universitaire de Biodiversité et Ecologie Microbienne (LUBEM), Université de Brest (UBO), Laboratoire de Virologie Humaine et Moléculaire [Caen], Laboratoire de biologie structurale des interactions entre virus et cellule hôte, Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, INSB-INSB-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie Physique et Microbiologie pour les Matériaux et l'Environnement (LCPME), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Génomique et épigénétique des pathologies placentaires (Inserm U709), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôtel-Dieu de Nantes, Centre d'Etudes Lasers Intenses et Applications (CELIA), Université de Bordeaux (UB)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], CHU Necker - Enfants Malades [AP-HP], Laboratoire de Virologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Service de Virologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), AgroParisTech, T1, Laboratoire Matériaux Optiques, Photonique et Systèmes (LMOPS), CentraleSupélec-Université de Lorraine (UL)-CentraleSupélec-Université de Lorraine (UL), Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sciences pour l'environnement (SPE), Université Pascal Paoli (UPP)-Centre National de la Recherche Scientifique (CNRS), Département d'infectiologie (CHU de Dijon), Centre d'Investigation Clinique Antilles-Guyane (CIC - Antilles Guyane), Université des Antilles et de la Guyane (UAG)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -CHU de Fort de France-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Laboratoire d'Acoustique de l'Université du Mans (LAUM), Centre National de la Recherche Scientifique (CNRS)-Le Mans Université (UM), ONERA - The French Aerospace Lab [Toulouse], ONERA, Service des maladies infectieuses et tropicales [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), UMR CNRS 8179, Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Sciences et Technologies, Service des maladies infectieuses et tropicales [CHU Pitié-Salpêtrière], Laboratoire Chrono-environnement - UFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Service de Médecine Interne, Maladies Infectieuses et Tropicales (POTIERS - Mal Inf), Service de Médecine interne, Maladies Infectieuses et Immunologie Clinique [Reims], Centre Hospitalier Universitaire de Reims (CHU Reims), Centre de Recherche en Cancérologie de Lyon (CRCL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches sur la Cognition Animale (CRCA), Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), University Hospital and University Jean Monnet, Laboratoire d'Ecologie Alpine (LECA), Centre National de la Recherche Scientifique (CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Université Joseph Fourier - Grenoble 1 (UJF)-Université Grenoble Alpes (UGA), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Biologie structurale des interactions entre virus et cellule hôte (UVHCI), Université Joseph Fourier - Grenoble 1 (UJF)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Bordeaux (UB), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Centre National de la Recherche Scientifique (CNRS)-Université Pascal Paoli (UPP), CHU de Fort de France-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française]-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles et de la Guyane (UAG), Université de Lille, Sciences et Technologies-Centre National de la Recherche Scientifique (CNRS), Laboratoire Chrono-environnement - CNRS - UFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Service de Médecine Interne, Maladies Infectieuses et Tropicales [CHU Poitiers], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut des sciences du cerveau de Toulouse. (ISCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Ecologie Alpine (LECA ), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Hôpital de la Pitié-Salpêtrière, Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC)
Subjects: 0301 basic medicine, Male, Drug Resistance, HIV Infections, Drug resistance, Medical and Health Sciences, chemistry.chemical_compound, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, 2.1 Biological and endogenous factors, Viral, Aetiology, Articles and Commentaries, ComputingMilieux_MISCELLANEOUS, minority resistant variants, Viral Load, Biological Sciences, first-line antiretroviral therapy, 3. Good health, Infectious Diseases, Rilpivirine, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, HIV/AIDS, Female, Infection, Viral hepatitis, Viral load, Microbiology (medical), Adult, ultra-deep sequencing, Microbiology, Virus, rilpivirine, 03 medical and health sciences, Acquired immunodeficiency syndrome (AIDS), Clinical Research, Drug Resistance, Viral, Genetics, medicine, Humans, business.industry, Genetic Variation, medicine.disease, Virology, Reverse transcriptase, Regimen, Good Health and Well Being, 030104 developmental biology, chemistry, Mutation, HIV-1, French National Agency for Research on AIDS and Viral Hepatitis (ANRS) AC11 Resistance Study Group, Antimicrobial Resistance, business
Abstract: Background Minority resistant variants of human immunodeficiency virus type 1 (HIV-1) could influence the virological response to treatment based on nonnucleoside reverse transcriptase inhibitors (NNRTIs). Data on minority rilpivirine-resistant variants are scarce. This study used next-generation sequencing (NGS) to identify patients harboring minority resistant variants to nucleos(t)ide reverse transcriptase inhibitors and NNRTIs and to assess their influence on the virological response (VR). Methods All the subjects, 541 HIV-1–infected patients started a first-line regimen containing rilpivirine. VR was defined as a HIV-1 RNA load Results NGS revealed resistance-associated mutations accounting for 1% to 20% in 29% of samples. We identified 43 (8.8%) and 36 (7.4%) patients who harbored rilpivirine-resistant variants with a 1% sensitivity threshold according to the French National Agency for Research on AIDS and Viral Hepatitis and Stanford algorithms, respectively. The VR was 96.9% at month 12. Detection of minority rilpivirine resistant variants was not associated with virological failure (VF). Multivariate analysis indicated that VF at month 12 was associated with a CD4 count Conclusions Minority resistant variants had no impact on the VR of treatment-naive patients to a rilpivirine-based regimen.
Published: 2018

15. Toward a transdiagnostic tool to evaluate depressive symptoms across mental disorders: Validation of the Calgary depression rating scale in patients with major depressive disorder

Author: Sébastien Weibel, Michel Cermolacce, Raphaëlle Richieri, Jean-Arthur Micoulaud-Franchi, Christophe Lançon, Catherine Faget, Mélanie Faugere, Sommeil, Attention et Neuropsychiatrie [Bordeaux] (SANPSY), Université de Bordeaux (UB)-CHU de Bordeaux Pellegrin [Bordeaux]-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neurosciences Cognitives [Marseille] (LNC), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'études et de recherche sur les services de santé et la qualité de vie (CEReSS), Aix Marseille Université (AMU), Laboratoire de santé publique évaluation des systèmes de soins et santé perçue, Sommeil, Addiction et Neuropsychiatrie [Bordeaux] (SANPSY), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Male, Psychometrics, Adolescent, 03 medical and health sciences, [SCCO]Cognitive science, Young Adult, 0302 clinical medicine, Rating scale, medicine, Humans, In patient, Young adult, Biological Psychiatry, Depressive symptoms, Depression (differential diagnoses), ComputingMilieux_MISCELLANEOUS, Aged, Aged, 80 and over, Psychiatric Status Rating Scales, Depressive Disorder, Major, business.industry, Reproducibility of Results, Middle Aged, medicine.disease, 030227 psychiatry, 3. Good health, Psychiatry and Mental health, Schizophrenia, Major depressive disorder, Female, business, 030217 neurology & neurosurgery, Clinical psychology
Abstract: The severity of depressive symptoms across two discrete mental disorders should be evaluated with the same psychometrically validated tools. In patients with schizophrenia the Calgary Depression Rating Scale (CDSS) is recommended for evaluating depressive symptoms. The aim of this study was to validate the CDSS in patients with major depressive disorder. The CDSS exhibit satisfactory psychometric properties for evaluating depressive symptoms in major depressive disorder. Clinicians and researchers now have a validated scale at their disposal to evaluate depressive symptoms in various mental disorders using a transdiagnostic approach.
Published: 2018

16. Hepatitis B Virus Evasion From Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase Sensing in Human Hepatocytes

Author: Julie Lucifora, Charlotte Bach, David Durantel, Eloi R. Verrier, Ivan Hirsch, Mirjam B. Zeisel, Seung-Ae Yim, Nicolas Manel, Nathalie Pochet, Laurent Mailly, Sarah C. Durand, Thomas F. Baumert, Patrick Pessaux, Houssein El Saghire, Laura Heydmann, Vincent Turon-Lagot, Catherine Schuster, Interactions Virus-Hôte et Maladies Hépatiques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Virologie, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle hépato-digestif [Strasbourg], Nouvel Hôpital Civil, Hospices Civils de Strasbourg-Institut Hospitalo-Universitaire de strasbourg, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de recherche Paris, sciences et lettres [Institut Curie, Paris], Institut Curie [Paris], Department of Genetics and Microbiology [Prague, Czech Republic] (Faculty of Science), Charles University [Prague] (CU), Department of Neurology [Cambridge, MA, USA] (Ann Romney Center for Neurologic Diseases), Harvard Medical School [Boston] (HMS)-Brigham and Women's Hospital [Boston], Cell Circuits Program [Cambridge, MA, USA], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by the European Union (ERC-AdG-2014-671231- HEPCIR, EU H2020-667273-HEPCAR, EU-InfectEra HepBccc), the National Institute of Health (NIAID 1R03AI131066-01A1, NCI R21 CA209940 and NIAID U19AI123862), the Agence Nationale de Recherches sur le Sida et les Hepatites Virales (ANRS, 2015/1099), the Fondation ARC pour la Recherche sur le Cancer (TheraHCC IHUARC IHU201301187), GACR 17-15422S, and a PhD fellowship of the Région Alsace, France. The work has been published under the framework of the LABEX ANR-10-LABX-0028_HEPSYS and benefits from funding from the state managed by the French National Research Agency as part of the Investments for the future program. E.R.V. was supported by an ANRS fellowship (ECTZ50121)., ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), Baumert, Thomas F., Initiative d'excellence - Par-delà les frontières, l'Université de Strasbourg - - UNISTRA2010 - ANR-10-IDEX-0002 - IDEX - VALID, and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Blotting, Western, Cell Culture Techniques, Guanosine, Biology, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Hepatocytes/metabolism/*virology, medicine.disease_cause, liver, Real-Time Polymerase Chain Reaction, Virus, Hepatitis B/immunology/*physiopathology, 03 medical and health sciences, chemistry.chemical_compound, Mice, Cyclic guanosine monophosphate–adenosine monophosphate, medicine, capsid, DNA, Viral/immunology, Hepatitis B virus/*pathogenicity, Humans, innate immunity, Hepatitis B virus, Innate immune system, Hepatology, Effector, In Situ Hybridization, Fluorescence/methods, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Virology, antiviral, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, Nucleotides, Cyclic/*metabolism, 030104 developmental biology, Real-time polymerase chain reaction, chemistry, Cell culture, Host-Pathogen Interactions, Immune Evasion/immunology/*physiology, recognition, Gene Expression Profiling/methods
Abstract: International audience; Chronic hepatitis B virus (HBV) infection is a major cause of chronic liver disease and cancer worldwide. The mechanisms of viral genome sensing and the evasion of innate immune responses by HBV infection are still poorly understood. Recently, the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) was identified as a DNA sensor. In this study, we investigated the functional role of cGAS in sensing HBV infection and elucidate the mechanisms of viral evasion. We performed functional studies including loss-of-function and gain-of-function experiments combined with cGAS effector gene expression profiling in an infectious cell culture model, primary human hepatocytes, and HBV-infected human liver chimeric mice. Here, we show that cGAS is expressed in the human liver, primary human hepatocytes, and human liver chimeric mice. While naked relaxed-circular HBV DNA is sensed in a cGAS-dependent manner in hepatoma cell lines and primary human hepatocytes, host cell recognition of viral nucleic acids is abolished during HBV infection, suggesting escape from sensing, likely during packaging of the genome into the viral capsid. While the hepatocyte cGAS pathway is functionally active, as shown by reduction of viral covalently closed circular DNA levels in gain-of-function studies, HBV infection suppressed cGAS expression and function in cell culture models and humanized mice. Conclusion: HBV exploits multiple strategies to evade sensing and antiviral activity of cGAS and its effector pathways.
Published: 2018

17. miR-135a-5p-mediated downregulation of protein tyrosine phosphatase receptor delta is a candidate driver of HCV-associated hepatocarcinogenesis

Author: Van Renne, Nicolaas, Roca Suarez, Armando Andres, Duong, Francois H T, Gondeau, Claire, Calabrese, Diego, Fontaine, Nelly, Ababsa, Amina, Bandiera, Simonetta, Croonenborghs, Tom, Pochet, Nathalie, De Blasi, Vito, Pessaux, Patrick, Piardi, Tullio, Sommacale, Daniele, Ono, Atsushi, Chayama, Kazuaki, Fujita, Masashi, Nakagawa, Hidewaki, Hoshida, Yujin, Zeisel, Mirjam B, Heim, Markus H, Baumert, Thomas F, Lupberger, Joachim, Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), University Hospital Basel [Basel], Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Harvard-MIT Division of Health Sciences and Technology [Cambridge], Massachusetts Institute of Technology (MIT), L'Institut hospitalo-universitaire de Strasbourg (IHU Strasbourg), Institut National de Recherche en Informatique et en Automatique (Inria)-l'Institut de Recherche contre les Cancers de l'Appareil Digestif (IRCAD)-Les Hôpitaux Universitaires de Strasbourg (HUS)-La Fédération des Crédits Mutuels Centre Est (FCMCE)-L'Association pour la Recherche contre le Cancer (ARC)-La société Karl STORZ, Université de Reims Champagne-Ardenne (URCA), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Hiroshima University, RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Interaction virus-hôte et maladies du foie, Philips, Alexandre, and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: Adult, Male, STAT3 Transcription Factor, Carcinoma, Hepatocellular, Carcinogenesis, [SDV]Life Sciences [q-bio], Blotting, Western, Aucun, Down-Regulation, Hepacivirus, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Humans, HEPATOCELLULAR CARCINOMA, RNA, Messenger, ComputingMilieux_MISCELLANEOUS, In Situ Hybridization, Fluorescence, Aged, Aged, 80 and over, Hepatology, Liver Neoplasms, Receptor-Like Protein Tyrosine Phosphatases, Class 2, Middle Aged, Hepatitis C, digestive system diseases, [SDV] Life Sciences [q-bio], MicroRNAs, Liver, SIGNALING, HCV, Hepatocytes, Female, Signal Transduction
Abstract: BACKGROUND AND AIMS: HCV infection is a leading risk factor of hepatocellular carcinoma (HCC). However, even after viral clearance, HCC risk remains elevated. HCV perturbs host cell signalling to maintain infection, and derailed signalling circuitry is a key driver of carcinogenesis. Since protein phosphatases are regulators of signalling events, we aimed to identify phosphatases that respond to HCV infection with relevance for hepatocarcinogenesis. METHODS: We assessed mRNA and microRNA (miRNA) expression profiles in primary human hepatocytes, liver biopsies and resections of patients with HCC, and analysed microarray and RNA-seq data from paired liver biopsies of patients with HCC. We revealed changes in transcriptional networks through gene set enrichment analysis and correlated phosphatase expression levels to patient survival and tumour recurrence. RESULTS: We demonstrate that tumour suppressor protein tyrosine phosphatase receptor delta (PTPRD) is impaired by HCV infection in vivo and in HCC lesions of paired liver biopsies independent from tissue inflammation or fibrosis. In liver tissue adjacent to tumour, high PTPRD levels are associated with a dampened transcriptional activity of STAT3, an increase of patient survival from HCC and reduced tumour recurrence after surgical resection. We identified miR-135a-5p as a mechanistic regulator of hepatic PTPRD expression in patients with HCV. CONCLUSIONS: We previously demonstrated that STAT3 is required for HCV infection. We conclude that HCV promotes a STAT3 transcriptional programme in the liver of patients by suppressing its regulator PTPRD via upregulation of miR-135a-5p. Our results show the existence of a perturbed PTPRD-STAT3 axis potentially driving malignant progression of HCV-associated liver disease.
Published: 2018

18. The functional role of sodium taurocholate cotransporting polypeptide NTCP in the life cycle of hepatitis B, C and D viruses

Author: Eloi R. Verrier, Carla Eller, Thomas F. Baumert, Catherine Schuster, Laura Heydmann, Che C. Colpitts, Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Interaction virus-hôte et maladies du foie, and AgroParisTech-Institut National de la Recherche Agronomique (INRA)
Subjects: 0301 basic medicine, Anti-viral therapy, Hepacivirus, Liver disease, Host factor, Symporters, Hepatitis B virus/*genetics/pathogenicity, virus diseases, Hepatitis B, Hepatitis C, Hepatitis D, Transmembrane protein, 3. Good health, Hepatocytes/pathology, Life Cycle Stages/genetics, Molecular Medicine, Hepatitis Delta Virus, Symporters/*genetics, Functional role, Hepatitis B virus, Hepatitis Delta Virus/*genetics/pathogenicity, Bile acid transport, Hepatitis C/genetics/virology, Organic Anion Transporters, Sodium-Dependent, Biology, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, digestive system, Article, Virus, 03 medical and health sciences, Cellular and Molecular Neuroscience, Immune system, medicine, Humans, Molecular Biology, Pharmacology, Life Cycle Stages, Hepatitis B/genetics/virology, Cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Cell Biology, Virus Internalization, medicine.disease, Virology, Hepatitis D/genetics/virology, Liver cell biology, 030104 developmental biology, Hepatocytes, Organic Anion Transporters, Sodium-Dependent/*genetics, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Chronic hepatitis B, C and D virus (HBV, HCV and HDV) infections are a major cause of liver disease and cancer worldwide. Despite employing distinct replication strategies, the three viruses are exclusively hepatotropic, and therefore depend on hepatocyte-specific host factors. The sodium taurocholate co-transporting polypeptide (NTCP), a transmembrane protein highly expressed in human hepatocytes that mediates the transport of bile acids, plays a key role in HBV and HDV entry into hepatocytes. Recently, NTCP has been shown to modulate HCV infection of hepatocytes by regulating innate antiviral immune responses in the liver. Here, we review the current knowledge of the functional role and the molecular and cellular biology of NTCP in the life cycle of the three major hepatotropic viruses, highlight the impact of NTCP as an antiviral target and discuss future avenues of research.
Published: 2018

19. Functional Study of the C-Terminal Part of the Hepatitis C Virus E1 Ectodomain

Author: Xavier Hanoulle, Gilles Duverlie, Thomas F. Baumert, Véronique Descamps, Jean Dubuisson, Juliano G Haddad, Muriel Lavie, Rehab I Moustafa, Ahmed Atef Ahmed Abouzeid Mesalam, Lydia Linna, Philip Meuleman, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), National Research Centre - NRC (EGYPT), Université Libanaise, Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Unité de Virologie clinique et fondamentale (UVCF), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Universiteit Gent = Ghent University (UGENT), Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie de Lille - UMS 3702 (IBL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Dubuisson, Jean, Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - UMR 8204 (CIIL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Unité de Virologie clinique et fondamentale EA 4294, Universiteit Gent [Ghent], Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Ghent University [Belgium] (UGENT), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), and Universiteit Gent = Ghent University [Belgium] (UGENT)
Subjects: 0301 basic medicine, hepatitis C virus, glycoprotein, Immunology, Mutant, DNA Mutational Analysis, Hepacivirus, Semliki Forest virus, Microbiology, Virus, Cell Line, viral assembly, 03 medical and health sciences, 0302 clinical medicine, Viral life cycle, Viral Envelope Proteins, Viral entry, Virology, Humans, envelope proteins, chemistry.chemical_classification, Infectivity, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, biology, Structure and Assembly, Virus Assembly, Virus Internalization, biology.organism_classification, 3. Good health, 030104 developmental biology, chemistry, Ectodomain, Insect Science, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Hepatocytes, 030211 gastroenterology & hepatology, Mutant Proteins, viral entry, Glycoprotein
Abstract: In the hepatitis C virus (HCV) envelope glycoproteins E1 and E2, which form a heterodimer, E2 is the receptor binding protein and the major target of neutralizing antibodies, whereas the function of E1 remains less characterized. To investigate E1 functions, we generated a series of mutants in the conserved residues of the C-terminal region of the E1 ectodomain in the context of an infectious clone. We focused our analyses on two regions of interest. The first region is located in the middle of the E1 glycoprotein (between amino acid [aa] 270 and aa 291), which contains a conserved hydrophobic sequence and was proposed to constitute a putative fusion peptide. The second series of mutants was generated in the region from aa 314 to aa 342 (the aa314-342 region), which has been shown to contain two α helices (α2 and α3) by nuclear magnetic resonance studies. Of the 22 generated mutants, 20 were either attenuated or noninfectious. Several mutations modulated the virus's dependence on claudin-1 and the scavenger receptor BI coreceptors for entry. Most of the mutations in the putative fusion peptide region affected virus assembly. Conversely, mutations in the α-helix aa 315 to 324 (315-324) residues M318, W320, D321, and M322 resulted in a complete loss of infectivity without any impact on E1E2 folding and on viral assembly. Further characterization of the W320A mutant in the HCVpp model indicated that the loss of infectivity was due to a defect in viral entry. Together, these results support a role for E1 in modulating HCV interaction with its coreceptors and in HCV assembly. They also highlight the involvement of α-helix 315-324 in a late step of HCV entry. IMPORTANCE HCV is a major public health problem worldwide. The virion harbors two envelope proteins, E1 and E2, which are involved at different steps of the viral life cycle. Whereas E2 has been extensively characterized, the function of E1 remains poorly defined. We characterized here the function of the putative fusion peptide and the region containing α helices of the E1 ectodomain, which had been previously suggested to be important for virus entry. We could confirm the importance of these regions for the virus infectivity. Interestingly, we found several residues modulating the virus's dependence on several HCV receptors, thus highlighting the role of E1 in the interaction of the virus with cellular receptors. Whereas mutations in the putative fusion peptide affected HCV infectivity and morphogenesis, several mutations in the α2-helix region led to a loss of infectivity with no effect on assembly, indicating a role of this region in virus entry.
Published: 2018

20. Fragile temporal prediction in patients with schizophrenia is related to minimal self disorders

Author: Martin, Brice, Franck, Nicolas, Cermolacce, Michel, Falco, Agnès, Benair, Anabel, Etienne, Estelle, Weibel, Sébastien, Coull, Jennifer T., Giersch, Anne, Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences Cognitives (ISC), Laboratoire de Neurosciences Cognitives [Marseille] (LNC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), GIERSCH, Anne, Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (ISC-MJ), and ANR-16-CE37-0004,AutoTime,Du codage automatique à la perception consciente du temps dans le système nerveux central: un déficit fondamental dans la schizophrénie?(2016)
Subjects: Adult, Male, Science, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Mental Status and Dementia Tests, Article, Young Adult, Cognition, Case-Control Studies, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Reaction Time, Schizophrenia, Humans, Medicine, Female, Schizophrenic Psychology, Cues, Symptom Assessment, ComputingMilieux_MISCELLANEOUS
Abstract: Patients with schizophrenia have difficulty in making sensory predictions, in the time domain, which have been proposed to be related to self-disorders. However experimental evidence is lacking. We examined both voluntary and automatic forms of temporal prediction in 28 patients and 24 matched controls. A visual cue predicted (temporal cue) or not (neutral cue) the time (400 ms/1000 ms) at which a subsequent target was presented. In both patients and controls, RTs were faster for targets presented after long versus short intervals due to the temporal predictability inherent in the elapse of time (“hazard function”). This RT benefit was correlated with scores on the EASE scale, which measures disorders of the self: patients with a high ‘self-awareness and presence’ score did not show any significant benefit of the hazard function, whereas this ability was preserved in patients with a low score. Moreover, all patients were abnormally sensitive to the presence of “catch” trials (unexpected absence of a target) within a testing block, with RTs actually becoming slower at long versus short intervals. These results indicate fragility in patients’ ability to continuously extract temporally predictive information from the elapsing interval. This deficit might contribute to perturbations of the minimal self in patients.
Published: 2017

21. Levels of intracellular HIV-DNA in patients with suppressive antiretroviral therapy

Author: Lise, Cuzin, Pascal, Pugliese, Karine, Sauné, Clotilde, Allavena, Jade, Ghosn, Jacqueline, Cottalorda, Audrey, Rodallec, Marie Laure, Chaix, Samira, Fafi-Kremer, Cathia, Soulié, Marlène, Ouka, Charlotte, Charpentier, Laurence, Bocket, Audrey, Mirand, Marguerite, Guiguet, S, Casanova, Hôpital Purpan, CHU Toulouse [Toulouse], Laboratory of Virology, Toulouse University hospital, Service de maladies infectieuses et tropicales [Nantes], Université de Nantes (UN)-Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire de Virologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], CHU Necker - Enfants Malades [AP-HP], Université Paris Descartes - Paris 5 (UPD5), Infection à VIH, réservoirs, diversité génétique et résistance aux antirétroviraux (ARV) (EA 7327), Université Sorbonne Paris Cité (USPC), Ecosystèmes Côtiers Marins et Réponses aux Stress (ECOMERS), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), Service de virologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Infections à Vih, Réservoirs, Pharmacologie des Antirétroviraux et Prévention de la Transmission Mère Enfant, Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidémiologie, stratégies thérapeutiques et virologie cliniques dans l'infection à VIH, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Virologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Laboratoire de virologie [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire Microorganismes : Génome et Environnement - Clermont Auvergne (LMGE), Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Laboratoire Microorganismes : Génome et Environnement (LMGE), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Université Nice Sophia Antipolis (1965 - 2019) (UNS), and Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Male, medicine.medical_specialty, Cross-sectional study, Immunology, HIV Infections, [SDV.MP.PRO]Life Sciences [q-bio]/Microbiology and Parasitology/Protistology, 03 medical and health sciences, 0302 clinical medicine, Interquartile range, Internal medicine, medicine, Humans, Immunology and Allergy, In patient, 030212 general & internal medicine, Viral suppression, Cd4 cell count, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, business.industry, Middle Aged, Viral Load, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Antiretroviral therapy, CD4 Lymphocyte Count, 3. Good health, Cross-Sectional Studies, Infectious Diseases, Increased risk, Anti-Retroviral Agents, DNA, Viral, Female, business, Viral load
Abstract: OBJECTIVE The objective of this study is to study factors associated with HIV-DNA levels in chronically infected patients on long-term suppressive antiretroviral therapy (ART). DESIGN A cross-sectional, multicentre study of patients receiving ART for more than 3 years, HIV-RNA less than 50 copies/ml for more than 2 years and CD4 cell count more than 350 cells/μl. METHOD Factors associated with low ( 1000), compared with intermediate (150-1000 copies/10 PBMCs) levels of HIV-DNA were investigated using multinomial logistic regression. RESULTS Five hundred and twenty-two patients who initiated ART during the chronic phase were included (71% male; median peak HIV-RNA: 4.88 log10 copies/ml, CD4 cell count nadir: 222 cells/μl). Median ART duration was 13 years [interquartile range (IQR) 7-17], viral suppression was 5.7 years (IQR 3.9-8.5) and 66% of the patients never experienced ART failure. Median HIV-DNA was 323 copies/10 PBMCs (IQR, 129-717) with low, intermediate and high levels observed in 28.3, 55.4 and 16.3%, respectively. In multivariable analysis, women were more likely to achieve a low level of HIV-DNA. Each additional year with suppressed HIV-RNA increased the likelihood of low level and decreased the likelihood of high level of HIV-DNA. Peak HIV-RNA higher than 5log10 was always associated with a decreased risk of low and an increased risk of high HIV-DNA. For patients with peak HIV-RNA lower than 5log10, past ART failure was associated with high level of HIV-DNA. CONCLUSION Chronically HIV-infected patients with long-term suppressive ART can achieve low total HIV-DNA but one over six still presented HIV-DNA above 1000 copies/10 PBMCs despite long-term viral suppression.
Published: 2015

22. Natural non-homologous recombination led to the emergence of a duplicated V3-NS5A region in HCV-1b strains associated with hepatocellular carcinoma

Author: Françoise Stoll-Keller, Henia Saoudin, Arielle A. Rosenberg, Dominique Bettinger, Pascal Veillon, Odile Petsaris, Cécile Henquell, Bruno Pozzetto, Catherine Gaudy-Graffin, Jean-Baptiste Bour, Sophie Minjolle-Cha, Jacques Izopet, Christopher Payan, E. Bouthry, Alexandra Ducancelle, Adeline Pivert, Hélène Le Guillou-Guillemette, Gisèle Lagathu, Sylvie Larrat, P. André, Anne Signori-Schmuck, Sophie Vallet, Françoise Lunel-Fabiani, Jean-Michel Pawlotsky, Yazid Baazia, Elisabeth André-Garnier, Christophe Lemaire, Florence Abravanel, Pascale Trimoulet, Sophie Alain, Vincent Thibault, Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), CHU Clermont-Ferrand, Laboratoire Microorganismes : Génome et Environnement (LMGE), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Laboratoire Universitaire de Biodiversité et Ecologie Microbienne (LUBEM), Université de Brest (UBO), Service de Bactériologie, Virologie, Hygiène [CHU Limoges], CHU Limoges, Anti-infectieux : supports moléculaires des résistances et innovations thérapeutiques (RESINFIT), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), CHU Pontchaillou [Rennes], Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Virologie de l'hépatite C (EA 4474), Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Cochin [AP-HP], Hôtel-Dieu de Nantes, Laboratoire de sérologie-virologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de bactériologie-Virologie-Hygiène [Avicenne], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Service de virologie et d'immunologie biologique, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH - U1259 Inserm - CHRU Tours ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Université Grenoble Alpes - UFR Pharmacie (UGA UFRP), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Groupe Immunité des Muqueuses et Agents Pathogènes (GIMAP), Université Jean Monnet - Saint-Étienne (UJM), Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut de Recherche en Horticulture et Semences (IRHS), Université d'Angers (UA)-Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Laboratoire Microorganismes : Génome et Environnement - Clermont Auvergne (LMGE), Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), CHU Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris 13 (UP13)-Hôpital Avicenne, Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Université Grenoble Alpes (UGA), Institut de biologie structurale (IBS - UMR 5075), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), Unit for Virus Host-Cell Interactions [Grenoble] (UVHCI), Université Joseph Fourier - Grenoble 1 (UJF)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Centre National de la Recherche Scientifique (CNRS), Université Jean Monnet [Saint-Étienne] (UJM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de la Recherche Agronomique (INRA)-Université d'Angers (UA), Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Avicenne, Université de Tours-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Institut National de la Santé et de la Recherche Médicale (INSERM), and AGROCAMPUS OUEST-Institut National de la Recherche Agronomique (INRA)-Université d'Angers (UA)
Subjects: RNA viruses, 0301 basic medicine, Mutant, lcsh:Medicine, Hepacivirus, Viral Nonstructural Proteins, Biochemistry, Cohort Studies, Database and Informatics Methods, Viral Envelope Proteins, Gene Duplication, Gene duplication, Evolutionary Emergence, lcsh:Science, Homologous Recombination, Pathology and laboratory medicine, Phylogeny, Data Management, Recombination, Genetic, Genetics, Multidisciplinary, Hepatitis C virus, Liver Neoplasms, Phylogenetic Analysis, Medical microbiology, Hepatitis C, 3. Good health, Nucleic acids, Phylogenetics, Viruses, Host-Pathogen Interactions, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Pathogens, Sequence Analysis, Recombination, Research Article, Computer and Information Sciences, Evolutionary Processes, Carcinoma, Hepatocellular, DNA recombination, Bioinformatics, 030106 microbiology, Viral quasispecies, Biology, Research and Analysis Methods, Microbiology, Viral Evolution, Evolution, Molecular, 03 medical and health sciences, Virology, Humans, Evolutionary Systematics, Gene, DNA sequence analysis, Taxonomy, Medicine and health sciences, Cloning, Evolutionary Biology, Polymorphism, Genetic, Biology and life sciences, Flaviviruses, lcsh:R, Organisms, Viral pathogens, RNA, Bayes Theorem, DNA, Hepatitis viruses, Organismal Evolution, Microbial pathogens, 030104 developmental biology, Genetic Loci, Microbial Evolution, Mutation, lcsh:Q, Homologous recombination, Sequence Alignment
Abstract: International audience; Background: The emergence of new strains in RNA viruses is mainly due to mutations or intra and inter-genotype homologous recombination. Non-homologous recombinations may be deleterious and are rarely detected. In previous studies, we identified HCV-1b strains bearing two tandemly repeated V3 regions in the NS5A gene without ORF disruption. This polymorphism may be associated with an unfavorable course of liver disease and possibly involved in liver carcinogenesis. Here we aimed at characterizing the origin of these mutant strains and identifying the evolutionary mechanism on which the V3 duplication relies.Methods: Direct sequencing of the entire NS5A and E1 genes was performed on 27 mutant strains. Quasispecies analyses in consecutive samples were also performed by cloning and sequencing the NS5A gene for all mutant and wild strains. We analyzed the mutant and wild-type sequence polymorphisms using Bayesian methods to infer the evolutionary history of and the molecular mechanism leading to the duplication-like event.Results: Quasispecies were entirely composed of exclusively mutant or wild-type strains respectively. Mutant quasispecies were found to have been present since contamination and had persisted for at least 10 years. This V3 duplication-like event appears to have resulted from non-homologous recombination between HCV-1b wild-type strains around 100 years ago. The association between increased liver disease severity and these HCV-1b mutants may explain their persistence in chronically infected patients.Conclusions: These results emphasize the possible consequences of non-homologous recombination in the emergence and severity of new viral diseases.
Published: 2017

23. Identification of Novel Functions for Hepatitis C Virus Envelope Glycoprotein E1 in Virus Entry and Assembly

Author: Thomas F. Baumert, Fouad Dabboussi, Xavier Hanoulle, Yves Rouillé, Jean Dubuisson, Monzer Hamze, Muriel Lavie, Juliano G. Haddad, Véronique Descamps, Gilles Duverlie, Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université Libanaise, Assemblage et réplication du virus de l'hépatite C (ARVHC), Centre National de la Recherche Scientifique (CNRS), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Unité de Virologie clinique et fondamentale EA 4294, CHU Amiens-Picardie, Centre AZM pour la Recherche en Biotechnologie et ses Applications, Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Université de Lille-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Unité de Virologie clinique et fondamentale (UVCF), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Institut de biologie de Lille - UMS 3702 (IBL), Université de Lille-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), and Dubuisson, Jean
Subjects: 0301 basic medicine, hepatitis C virus, glycoprotein, Protein Folding, Hepatitis C virus, Immunology, DNA Mutational Analysis, Mutation, Missense, Hepacivirus, Biology, medicine.disease_cause, Microbiology, Virus, Cell Line, viral assembly, 03 medical and health sciences, 0302 clinical medicine, Viral life cycle, Viral envelope, Viral Envelope Proteins, Glycoprotein complex, Viral entry, Virology, medicine, Humans, envelope proteins, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Virus Assembly, Structure and Assembly, Virus Internalization, Herpesvirus glycoprotein B, 3. Good health, 030104 developmental biology, Ectodomain, Insect Science, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Hepatocytes, Receptors, Virus, 030211 gastroenterology & hepatology, viral entry, Protein Multimerization
Abstract: Hepatitis C virus (HCV) envelope glycoprotein complex is composed of E1 and E2 subunits. E2 is the receptor-binding protein as well as the major target of neutralizing antibodies, whereas the functions of E1 remain poorly defined. Here, we took advantage of the recently published structure of the N-terminal region of the E1 ectodomain to interrogate the functions of this glycoprotein by mutating residues within this 79-amino-acid region in the context of an infectious clone. The phenotypes of the mutants were characterized to determine the effects of the mutations on virus entry, replication, and assembly. Furthermore, biochemical approaches were also used to characterize the folding and assembly of E1E2 heterodimers. Thirteen out of 19 mutations led to viral attenuation or inactivation. Interestingly, two attenuated mutants, T213A and I262A, were less dependent on claudin-1 for cellular entry in Huh-7 cells. Instead, these viruses relied on claudin-6, indicating a shift in receptor dependence for these two mutants in the target cell line. An unexpected phenotype was also observed for mutant D263A which was no longer infectious but still showed a good level of core protein secretion. Furthermore, genomic RNA was absent from these noninfectious viral particles, indicating that the D263A mutation leads to the assembly and release of viral particles devoid of genomic RNA. Finally, a change in subcellular colocalization between HCV RNA and E1 was observed for the D263A mutant. This unique observation highlights for the first time cross talk between HCV glycoprotein E1 and the genomic RNA during HCV morphogenesis. IMPORTANCE Hepatitis C virus (HCV) infection is a major public health problem worldwide. It encodes two envelope proteins, E1 and E2, which play a major role in the life cycle of this virus. E2 has been extensively characterized, whereas E1 remains poorly understood. Here, we investigated E1 functions by using site-directed mutagenesis in the context of the viral life cycle. Our results identify unique phenotypes. Unexpectedly, two mutants clearly showed a shift in receptor dependence for cell entry, highlighting a role for E1 in modulating HCV particle interaction with a cellular receptor(s). More importantly, another mutant led to the assembly and release of viral particles devoid of genomic RNA. This unique phenotype was further characterized, and we observed a change in subcellular colocalization between HCV RNA and E1. This unique observation highlights for the first time cross talk between a viral envelope protein and genomic RNA during morphogenesis.
Published: 2017

24. Chronic hepatitis C virus infection and pathogenesis of hepatocellular carcinoma

Author: Mirjam B. Zeisel, Thomas F. Baumert, Simonetta Bandiera, C Billie Bian, Yujin Hoshida, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Interaction virus-hôte et maladies du foie, and Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Liver Cirrhosis, 0301 basic medicine, Carcinoma, Hepatocellular, Cirrhosis, Hepatitis C virus, Biology, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, medicine.disease_cause, Models, Biological, Article, Virus, Pathogenesis, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Virology, medicine, Carcinoma, Humans, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Hepatitis C, Hepatitis C, Chronic, medicine.disease, digestive system diseases, 3. Good health, 030104 developmental biology, Hepatocellular carcinoma, Immunology, 030211 gastroenterology & hepatology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Hepatitis C virus (HCV) infection is one of the major causes of advanced liver disease and hepatocellular carcinoma (HCC) worldwide. While the knowledge about the molecular virology of HCV infection has markedly advanced, the molecular mechanisms of disease progression leading to fibrosis, cirrhosis and HCC are still unclear. Accumulating experimental and clinical studies indicate that HCV may drive hepatocarcinogenesis directly via its proteins or transcripts, and/or indirectly through induction of chronic liver inflammation. Despite the possibility to eradicate HCV infection through direct-acting antiviral treatment, the risk of HCC persists although specific biomarkers to estimate this risk are still missing. Thus, a better understanding of HCV-induced HCC and more physiological liver disease models are required to prevent cancer development.
Published: 2016

25. Nouveaux rôles de l'apolipoprotéine E dans le cycle du virus de l'hépatite C : Docteur Jekyll ou Mister Hyde ?

Author: Crouchet, Émilie, Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Strasbourg, Catherine Schuster, and STAR, ABES
Subjects: [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, ABCG1, Lipid metabolism, HDL, Hepatitis C virus, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Anticorps neutralisants, lipids (amino acids, peptides, and proteins), Apolipoprotein E, Neutralizing antibodies, Métabolisme des lipides, Apolipoprotéine E, Virus de l’hépatite C
Abstract: Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma worldwide. Understanding virus-host interactions in hepatocytes will contribute towards the development of new therapeutic strategies and a protective vaccine. HCV life cycle and the lipid metabolism are inextricably intertwined. A particular feature of this virus is that, in the blood, HCV virions are associated with lipoproteins, forming an infectious lipoviroparticle (LVP). Apolipoprotein E (apoE) is a key component of LVPs that plays an essential role in HCV entry and virions production. My PhD project entailed a more detailed dissection of apoE’s role in the HCV life cycle. I demonstrated that lipid-free apoE inhibits HCV replication by regulating the hepatic lipid metabolism via an ABCG1-dependent cholesterol efflux. Furthermore, I contributed to a study demonstrating that LVP-associated apoE helps the virus escape host immunity by blocking access of neutralizing antibodies to the viral glycoprotein E2. The work presented highlights two new roles of apoE in HCV pathogenesis, L’infection par le virus de l’hépatite C (HCV) est une cause majeure d’hépatite chronique, de cirrhose hépatique et ce carcinome hépatocellulaire dans le monde. La compréhension des relations entre le virus et sa cellule hôte, l’hépatocyte, est indispensable pour le développement de nouvelles stratégies thérapeutiques et d’un vaccin préventif. La particularité de ce virus est son lien étroit avec le métabolisme lipidique. Le virus circule dans le sang associé aux lipoprotéines, formant une lipo-viro-particule (LVP) infectieuse. L’apolipoprotéine E (apoE) est une protéine cellulaire faisant intégralement partie de la LVP. Elle joue un rôle majeur dans l’infection et à la production des particules virales. Durant ce travail de thèse, j’ai pu approfondir les connaissances sur le rôle d’apoE dans le cycle viral du HCV sous deux aspects très différents. D’une part, j’ai pu démontré que la forme libre d’apoE, non liée aux lipoprotéines, inhibe la réplication du HCV grâce à la régulation du métabolisme lipidique hépatique, en induisant un efflux de cholestérol ABCG1-dépendant. D’autre part, j’ai participé à une étude démontrant que l’apoE liée à la LVP contribue à l’échappement du virus au système immunitaire, en masquant les épitopes de la protéine virale E2 aux anticorps neutralisants. Ces études ont mis en évidence deux nouveaux rôles d’apoE dans la pathogenèse du HCV.
Published: 2016

26. Hepatitis C virus cell entry: a target for novel antiviral strategies to address limitations of direct acting antivirals

Author: Che C. Colpitts, Thomas F. Baumert, Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Interaction virus-hôte et maladies du foie, and daulny, anne
Subjects: 0301 basic medicine, medicine.medical_specialty, Hepatitis C virus, [SDV]Life Sciences [q-bio], Hepacivirus, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Bioinformatics, medicine.disease_cause, Antiviral Agents, Article, 03 medical and health sciences, Liver disease, Viral entry, Internal medicine, medicine, Global health, Animals, Humans, Cell entry, Clinical Trials as Topic, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Hepatology, business.industry, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Hepatitis C, Chronic, Virus Internalization, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Treatment Outcome, Hepatocellular carcinoma, Immunology, Liver cancer, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Hepatitis C virus (HCV) infection remains a major global health problem, with 130-170 million chronically infected individuals at risk to develop severe liver disease, including hepatocellular carcinoma. Although the development of direct-acting antivirals offers cure for a large majority of patients, there are still a number of clinical challenges. These include DAA failure in a significant subset of patients, difficult-to-treat genotypes and limited access to therapy due to high costs. Moreover, recent data indicate that the risk for liver cancer persists in patients with advanced fibrosis. These challenges highlight the need for continued efforts towards novel therapeutic strategies for HCV. Over the past two decades, advances in HCV model systems have enabled a detailed understanding of HCV entry and its clinical impact. Many of the virus-host interactions involved in HCV entry have now been identified and explored as antiviral targets. Furthermore, viral entry is recognized as an important factor for graft reinfection and establishment of persistent infection. HCV entry inhibitors, therefore, offer promising opportunities to address the limitations of DAAs. Here, we summarize recent advances in the field of HCV entry and discuss perspectives towards the prevention and cure of HCV infection and virus-induced liver disease.
Published: 2016

27. Towards a new standardized method for circulating miRNAs profiling in clinical studies: Interest of the exogenous normalization to improve miRNA signature accuracy

Author: Jean-Paul Issartel, Audrey Guttin, Laurent Poulain, Yannick Lecluse, Pierre Lebailly, Matthieu Meryet-Figuière, Bénédicte Clarisse, Mélanie Briand, Nicolas Vigneron, Stephanie Lheureux, Marie-Hélène Louis, Bernard Lambert, Florence Joly, Christophe Denoyelle, Pascal Gauduchon, Sophie Krieger, Mégane Vernon, Alexandra Leconte, Biologie et Thérapies Innovantes des Cancers Localement Agressifs (BioTICLA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Cancers et préventions, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Oncologie médicale [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche clinique [CHU Caen] (CRC), Normandie Université (NU)-Normandie Université (NU)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), POULAIN, Laurent, Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), and Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER
Subjects: 0301 basic medicine, Mirna signature, Circulating mirnas, Normalization (statistics), Serum, Cancer Research, Microarray, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, Real-Time Polymerase Chain Reaction, Bioinformatics, Article, 03 medical and health sciences, Plasma, [SDV.CAN] Life Sciences [q-bio]/Cancer, Ovarian cancer, Neoplasms, microRNA, Genetics, Circulating miRNA, Humans, Medicine, Profiling (information science), Oligonucleotide Array Sequence Analysis, business.industry, Gene Expression Profiling, Profiling, Articles, General Medicine, Reference Standards, 3. Good health, Gene Expression Regulation, Neoplastic, Clinical Practice, [SDV] Life Sciences [q-bio], MicroRNAs, Normalization, 030104 developmental biology, Oncology, Molecular Medicine, DNA microarray, business
Abstract: Circulating miRNAs are promising biomarkers in oncology but have not yet been implemented in the clinic given the lack of concordance across studies. In order to increase the cross‐studies reliability, we attempted to reduce and to control the circulating miRNA expression variability between patients. First, to maximize profiling signals and to reduce miRNA expression variability, three isolation kits were compared and the NucleoSpin® kit provided higher miRNA concentrations than the other widely used kits. Second, to control inter‐sample variability during the profiling step, the exogenous miRNAs normalization method commonly used for RT‐qPCR validation step was adapted to microarray experiments. Importantly, exogenous miRNAs presented two‐fold lower inter‐sample variability than the widely used endogenous miR‐16‐5p reflecting that the latter is subject to both biological and technical variability. Although Caenorhabditis elegans miRNAs isolation yields were heterogeneous, they correlated to each other and to their geometrical mean across samples. The normalization based on the geometrical mean of three exogenous miRNAs increased the correlation up‐to 0.97 between the microarrays and individual RT‐qPCR steps of circulating miRNAs expression. Overall, this new strategy open new avenue to identify reliable circulating miRNA signatures for translation into clinical practice., Highlights NucleoSpin kit offers the highest endogenous miRNA concentrations from serum/plasma.A common normalization based on exogenous miRNAs for discovery and validation steps.New strategy to increase both the signature accuracy and the overlap across studies.
Published: 2016

28. Autotaxin-lysophosphatidic acid receptor signalling regulates hepatitis C virus replication

Author: Michael J.O. Wakelam, Jane A. McKeating, Thomas F. Baumert, Simon A. Rudge, Maria Ciaccia, Laurent Mailly, Ke Hu, Margaret Ashcroft, Isla S. Humphreys, Stephanie Roessler, Bishnupriya Bhattacharya, Qifeng Zhang, Garrick K. Wilson, Michelle J. Farquhar, Gary M. Reynolds, Peter Balfe, Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), NIHR Liver Biomedical Research Unit, University of Birmingham [Birmingham], Interaction virus-hôte et maladies du foie, Hepatitis C Research Group, Institute for Biomedical Research-University of Birmingham [Birmingham], Rudge, Simon Alan [0000-0003-2172-9709], Ashcroft, Margaret [0000-0002-0066-3707], Wakelam, Michael [0000-0003-4059-9276], and Apollo - University of Cambridge Repository
Subjects: autotaxin, hepatitis C virus, 0301 basic medicine, Hepatitis C virus, [SDV]Life Sciences [q-bio], lipid signalling, Lysophosphatidic Acid Receptor, Hepacivirus, Biology, medicine.disease_cause, Virus Replication, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, Mice, Lysophosphatidic acid, medicine, Animals, Humans, RNA, Messenger, Receptors, Lysophosphatidic Acid, Promoter Regions, Genetic, ComputingMilieux_MISCELLANEOUS, Hepatology, hypoxia, Phosphoric Diester Hydrolases, Liver Neoplasms, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Hepatitis C, Chronic, Hypoxia-Inducible Factor 1, alpha Subunit, Virology, digestive system diseases, 3. Good health, 030104 developmental biology, chemistry, Autotaxin, lysophosphatidic acid, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Signal Transduction
Abstract: BACKGROUND AND AIMS: Chronic hepatitis C is a global health problem with an estimated 170 million HCV infected individuals at risk of progressive liver disease and hepatocellular carcinoma (HCC). Autotaxin (ATX) is a phospholipase with diverse roles in physiological and pathological processes including inflammation and oncogenesis. Clinical studies have reported increased ATX expression in chronic hepatitis C, however, the pathways regulating ATX and its role in the viral life cycle are not well understood. METHODS: In vitro hepatocyte and ex vivo liver culture systems along with chimeric humanized liver mice and HCC tissue enabled us to assess the interplay between ATX and the HCV life cycle. RESULTS: HCV infection increased hepatocellular ATX RNA and protein expression. HCV infection stabilizes hypoxia inducible factors (HIFs) and we investigated a role for these transcription factors to regulate ATX. In vitro studies show that low oxygen increases hepatocellular ATX expression and transcriptome analysis showed a positive correlation between ATX mRNA levels and hypoxia gene score in HCC tumor tissue associated with HCV and other aetiologies. Importantly, inhibiting ATX-lysophosphatidic acid (LPA) signalling reduced HCV replication, demonstrating a positive role for this phospholipase in the viral life cycle. LPA activates phosphoinositide-3-kinase that stabilizes HIF-1α and inhibiting the HIF-signalling pathway abrogates the pro-viral activity of LPA. CONCLUSIONS: Our data support a model where HCV infection increases ATX expression that supports viral replication and HCC progression. LAY SUMMARY: Chronic hepatitis C is a global health problem with infected individuals at risk of developing liver disease that can progress to hepatocellular carcinoma. Autotaxin generates the biologically active lipid lysophosphatidic acid that has been reported to play a tumorigenic role in a wide number of cancers. In this study we show that Hepatitis C virus infection increases autotaxin expression via hypoxia inducible transcription factor and provides an environment in the liver that promotes fibrosis and liver injury. Importantly, we show a new role for lysophosphatidic acid in positively regulating hepatitis C virus replication.
Published: 2016

29. The HSP90 inhibitor, 17AAG, protects the intestinal stem cell niche and inhibits graft versus host disease development

Author: Arlette Hammann, Eric Solary, Oleg N. Demidov, Gaëtan Jego, Robinet E, A. Seignez, Sarah Richaud, Anastasia R. Goloudina, Evelyne Kohli, Magali Svrcek, Carmen Garrido, Eric Fourmaux, Deepti A, Anne-Laure Joly, Sophie Hébrard, Ada Collura, Elise Schmitt, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hématopoïèse normale et pathologique, Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)-Université de Montpellier (UM), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Montpellier (UM), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer ( LabEx LipSTIC ), Institut National de la Recherche Agronomique ( INRA ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Université Paris-Sud - Paris 11 ( UP11 ) -École pratique des hautes études ( EPHE ) -Institut Gustave Roussy ( IGR ) -Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ) -Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université de Franche-Comté ( UFC ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), and UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC)
Subjects: 0301 basic medicine, X-Box Binding Protein 1, Cancer Research, Lactams, Macrocyclic, RNA Splicing, T-Cells, Graft vs Host Disease, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Hsp90 inhibitor, 03 medical and health sciences, Mice, Sensitivity, Inflammatory-Bowel-disease, Genetics, medicine, Benzoquinones, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Neural progenitor cells, HSP90 Heat-Shock Proteins, Intestinal Mucosa, Stem Cell Niche, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, Leukemia, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, Bone-Marrow-Transplantation, Molecules, medicine.disease, Stem cell niche, 3. Good health, Ire1-Alpha, Intestines, Mice, Inbred C57BL, 030104 developmental biology, Graft-versus-host disease, Er Stress, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Cytoprotection, Immunology, Multiple-Myeloma, Female
Abstract: IF 7.932; International audience; Graft versus host disease (GvHD), which is the primary complication of allogeneic bone marrow transplantation, can alter the intestinal barrier targeted by activated donor T-cells. Chemical inhibition of the stress protein HSP90 was demonstrated in vitro to inhibit T-cell activation and to modulate endoplasmic reticulum (ER) stress to which intestinal cells are highly susceptible. Since the HSP90 inhibitor 17-allylamino-demethoxygeldanamycin (17AAG) is developed in clinics, we explored here its ability to control intestinal acute GvHD in vivo in two mouse GvHD models (C57BL/6 -> BALB/c and FVB/N -> Lgr5-eGFP), ex vivo in intestine organoids and in vitro in intestinal epithelial cultures. We show that 17AAG decreases GvHD-associated mortality without impairing graft versus leukemia effect. While 17AAG effect in T-cell activation is just moderate at the dose used in vivo, we observe a striking intestinal integrity protection. At the intestine level, the drug promotes the splicing of the transcription factor X-box binding protein 1 (XBP1), which is a key component of the ER stress. This effect is associated with a decrease in intestinal damage and an increase in Lgr5(+) stem cells, Paneth cells and defensins production. The importance of XBP1 splicing control is further confirmed in cultured cells and organoids of primary intestinal epithelium where XBP1 is either shRNA depleted or inhibited with toyocamycin. In conclusion, 17AAG has a protective effect on the epithelial intestinal barrier in mouse models of acute GvHD. This compound deserves to be tested in the therapeutic control of acute GvHD.
Published: 2016

30. Unraveling Hepatitis C virus-induced biological circuits contributing to the development of hepatocellular carcinoma

Author: Van Renne, Nicolaas, STAR, ABES, Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Strasbourg, Thomas Baumert, and Mirjam Zeisel
Subjects: [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Hepatitis C virus, Hepatocellular carcinoma, Maladie hépatique, PTPRD, Carcinome hépatocellulaire, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Signalisation cellulaire, Phosphatase, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Liver disease, Cell signalling, Virus de l’hépatite C
Abstract: By combining a cell culture system of hepatocyte-like cells with purified hepatitis C virus (HCV), we effectively simulated chronic infection in vitro. We found this infection model induces a transcriptomic profile of chronic HCV patients at high risk of developing hepatocellular carcinoma (HCC). Using this model, we have uncovered the functional role of EGFR as a driver of the HCC risk signature and revealed candidate drivers of the molecular recalibration of hepatocytes leading to liver cancer. In an approach to study liver disease in vivo, we opted to screen for protein phosphatase expression in liver biopsies of chronic HCV patients. We observed a downregulation of PTPRD, a well-known tumor suppressor. We demonstrated that this effect is mediated by an increase in miR-135a-5p which targets PTPRD mRNA. Moreover, in silico analysis shows that PTPRD expression in adjacent liver tissue of HCC patients correlates with survival and reduced tumor recurrence after surgical resection., En combinant un nouveau système de culture cellulaire à partir d'hépatocytes différenciés avec du virus de l’hépatite C (VHC) purifié, nous pouvons induire un profil transcriptomique caractéristique des patients à risque élevé de développer un carcinome hépatocellulaire (CHC). En utilisant ce modèle, nous avons découvert le rôle fonctionnel de l'EGFR comme élément moteur de la signature du risque de développement d'un CHC. De plus, nous avons identifié des gènes candidats impliqués dans le développement du CHC. Pour étudier les maladies du foie in vivo, nous avons caractérisé l'expression des protéines phosphatases dans des biopsies hépatiques de patients infectés par le VHC. Nous avons observé une régulation négative de PTPRD, un suppresseur de tumeur, causé par une augmentation de miR-135a-5p qui cible l'ARNm de PTPRD. Par ailleurs, l'analyse in silico montre que l'expression de PTPRD dans le tissu hépatique est corrélée à la survie chez les patients atteints de CHC.
Published: 2016

31. Characterization of Hepatitis C Virus Particle Subpopulations Reveals Multiple Usage of the Scavenger Receptor BI for Entry Steps

Author: Marlène Dreux, Ophélia Granio, Thomas F. Baumert, Ralf Bartenschlager, Maryse Guerin, Christelle Granier, François-Loïc Cosset, François Penin, Mirjam B. Zeisel, Viet Loan Dao Thi, Dimitri Lavillette, Jimmy Mancip, Virologie humaine, École normale supérieure - Lyon (ENS Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medicine II, University of Freiburg [Freiburg], Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Department of Molecular Virology (DMV), Universität Heidelberg [Heidelberg], Plate-forme de R&D - Puces à Cellules Transfectées (PCT), Cancéropôle du Grand-Est (CGE)-Centre Européen de Biologie et de Génomique Structurale (CEBGS), Naiglin, Laurence, Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure de Lyon (ENS de Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Bases moléculaires et structurales des systèmes infectieux (BMSSI), Universität Heidelberg [Heidelberg] = Heidelberg University, Virus, mmunité innée et trafic vésiculaire - Vesicular trafficking, innate response and viruses (VIV), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Référent HAL, CIRI, Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL)
Subjects: Apolipoprotein E, Very low-density lipoprotein, MESH: Virus Internalization, Hepacivirus, medicine.disease_cause, Biochemistry, MESH: Protein Structure, Tertiary, Mice, 0302 clinical medicine, Viral Envelope Proteins, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Animals, MESH: Hepacivirus, Receptor, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, chemistry.chemical_classification, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, virus diseases, Scavenger Receptors, Class B, MESH: Apolipoproteins E, 3. Good health, Cell biology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, lipids (amino acids, peptides, and proteins), 030211 gastroenterology & hepatology, MESH: Cell Line, Tumor, MESH: Rats, Viral protein, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Biology, Microbiology, Apolipoproteins E, 03 medical and health sciences, Cell Line, Tumor, medicine, Animals, Humans, Scavenger receptor, MESH: Mice, Molecular Biology, 030304 developmental biology, MESH: Humans, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Cell Biology, Virus Internalization, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Scavenger Receptors, Class B, digestive system diseases, Protein Structure, Tertiary, Rats, chemistry, MESH: Viral Envelope Proteins, Glycoprotein, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Lipoprotein
Abstract: International audience; Hepatitis C virus (HCV) particles assemble along the very low density lipoprotein pathway and are released from hepatocytes as entities varying in their degree of lipid and apolipoprotein (apo) association as well as buoyant densities. Little is known about the cell entry pathway of these different HCV particle subpopulations, which likely occurs by regulated spatiotemporal processes involving several cell surface molecules. One of these molecules is the scavenger receptor BI (SR-BI), a receptor for high density lipoprotein that can bind to the HCV glycoprotein E2. By studying the entry properties of infectious virus subpopulations differing in their buoyant densities, we show that these HCV particles utilize SR-BI in a manifold manner. First, SR-BI mediates primary attachment of HCV particles of intermediate density to cells. These initial interactions involve apolipoproteins, such as apolipoprotein E, present on the surface of HCV particles, but not the E2 glycoprotein, suggesting that lipoprotein components in the virion act as host-derived ligands for important entry factors such as SR-BI. Second, we found that in contrast to this initial attachment, SR-BI mediates entry of HCV particles independent of their buoyant density. This function of SR-BI does not depend on E2/SR-BI interaction but relies on the lipid transfer activity of SR-BI, probably by facilitating entry steps along with other HCV entry co-factors. Finally, our results underscore a third function of SR-BI governed by specific residues in hypervariable region 1 of E2 leading to enhanced cell entry and depending on SR-BI ability to bind to E2.
Published: 2012

32. Contribution of bioinformatics predictions and functional splicing assays to the interpretation of unclassified variants of the BRCA genes

Author: Pascaline Berthet, Audrey Killian, Sophie Krieger, Dominique Vaur, Thierry Frebourg, Jean Christophe Thery, Mario Tosi, Pascaline Gaildrat, Alexandra Martins, Françoise Révillion, Agnès Hardouin, Antoine Rousselin, Christiane Duponchel, Jean-Philippe Peyrat, Marie-Pierre Buisine, Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Oncologie Moléculaire Humaine, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Inserm U614, IFRMP, Faculty of Medicine and Department of Genetics, University Hospital, Institute for Biomedical Research and Innovation, Rouen, France, Laboratoire de biologie clinique et oncologique, UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Université de Lille-UNICANCER-Université de Lille-UNICANCER, Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), and Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)
Subjects: endocrine system diseases, RNA Splicing, [SDV]Life Sciences [q-bio], Genes, BRCA2, Genes, BRCA1, Exonic splicing enhancer, Breast Neoplasms, Biology, Bioinformatics, Article, 03 medical and health sciences, Exon, 0302 clinical medicine, Genes, Reporter, Predictive Value of Tests, Genetics, Humans, splice, RNA, Messenger, skin and connective tissue diseases, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), 030304 developmental biology, BRCA2 Protein, Ovarian Neoplasms, 0303 health sciences, Splice site mutation, BRCA1 Protein, Intron, Computational Biology, Genetic Variation, Exon skipping, 3. Good health, 030220 oncology & carcinogenesis, RNA splicing, Female, RNA Splice Sites, Minigene
Abstract: A large fraction of sequence variants of unknown significance (VUS) of the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 may induce splicing defects. We analyzed 53 VUSs of BRCA1 or BRCA2, detected in consecutive molecular screenings, by using five splicing prediction programs, and we classified them into two groups according to the strength of the predictions. In parallel, we tested them by using functional splicing assays. A total of 10 VUSs were predicted by two or more programs to induce a significant reduction of splice site strength or activation of cryptic splice sites or generation of new splice sites. Minigene-based splicing assays confirmed four of these predictions. Five additional VUSs, all at internal exon positions, were not predicted to induce alterations of splice sites, but revealed variable levels of exon skipping, most likely induced by the modification of exonic splicing regulatory elements. We provide new data in favor of the pathogenic nature of the variants BRCA1 c.212+3A>G and BRCA1 c.5194−12G>A, which induced aberrant out-of-frame mRNA forms. Moreover, the novel variant BRCA2 c.7977−7C>G induced in frame inclusion of 6 nt from the 3′ end of intron 17. The novel variants BRCA2 c.520C>T and BRCA2 c.7992T>A induced incomplete skipping of exons 7 and 18, respectively. This work highlights the contribution of splicing minigene assays to the assessment of pathogenicity, not only when patient RNA is not available, but also as a tool to improve the accuracy of bioinformatics predictions.
Published: 2011

33. EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy

Author: Michel Doffoel, Marine Turek, Isabel Fofana, Olivier Poch, Muhammad N. Zahid, Patrick Pessaux, Thomas F. Baumert, Fei Xiao, Laetitia Zona, Christopher Davis, Sebastian Gorke, S. Michael Rothenberg, François-Loïc Cosset, Mirjam B. Zeisel, Laurent Brino, Dimitri Lavillette, Cathy Royer, Thomas Pietschmann, Wolfgang Raffelsberger, Benoit Fischer, Jane A. McKeating, Judith Fresquet, Christopher J. Mee, Arvind H. Patel, Joachim Lupberger, Christine Thumann, Baumert, Thomas F., Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hepatitis C Research Group, Division of Immunity and Infection-University of Birmingham [Birmingham], Department of Medicine II, University of Freiburg [Freiburg], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Virologie humaine, École normale supérieure - Lyon (ENS Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Massachusetts General Hospital Cancer Center, Howard Hughes Medical Institute (HHMI)-Harvard Medical School [Boston] (HMS), Division of Experimental Virology, Centre for Experimental and Clinical Infection Research (TWINCORE), Helmholtz Centre for Infection Research (HZI)-Medizinische Hochschule Hannover (MHH)-Helmholtz Centre for Infection Research (HZI)-Medizinische Hochschule Hannover (MHH), MRC Virology Unit, University of Glasgow, Service d'Hépato-gastroentérologie, Hôpitaux Universitaires de Strasbourg-Nouvel Hôpital Civil, ERC-2008-AdG-233130-HEPCENT, INTERREG-IV-Rhin Supérieur-FEDER-Hepato-Regio-Net 2009, ANR-05-CEXC-008, ANRS 2008/354, Région Alsace, INCa, NIH, MRC and the Wellcome Trust., École normale supérieure de Lyon (ENS de Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)
Subjects: MESH: Virus Internalization, Hepacivirus, MESH: Base Sequence, Ligands, medicine.disease_cause, Receptor tyrosine kinase, Mice, Cell-cell transmission, 0302 clinical medicine, Claudin-1, MESH: RNA, Small Interfering, MESH: Ligands, MESH: Protein Kinase Inhibitors, MESH: Animals, MESH: Hepacivirus, Epidermal growth factor receptor, RNA, Small Interfering, MESH: Antigens, CD, MESH: Receptor, EphA2, 0303 health sciences, Phosphotyrosine kinase, biology, Receptor, EphA2, virus diseases, General Medicine, EPH receptor A2, Hepatitis C, 3. Good health, ErbB Receptors, MESH: Quinazolines, Liver, Host-Pathogen Interactions, RNA Interference, 030211 gastroenterology & hepatology, MESH: Membrane Proteins, Tyrosine kinase, MESH: Antiviral Agents, Hepatitis C virus, MESH: RNA Interference, MESH: Receptor, Epidermal Growth Factor, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Antiviral Agents, Article, General Biochemistry, Genetics and Molecular Biology, Cell Line, Tetraspanin 28, Erlotinib Hydrochloride, 03 medical and health sciences, MESH: Antigens, CD81, Antigens, CD, Viral entry, medicine, Animals, Humans, Antiviral, Kinase activity, Protein Kinase Inhibitors, MESH: Mice, 030304 developmental biology, MESH: Hepatitis C, MESH: Humans, Base Sequence, MESH: Host-Pathogen Interactions, Erythropoietin-producing hepatocellular (Eph) receptor, Membrane Proteins, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Virus Internalization, Virology, digestive system diseases, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Cell Line, HCV escape variants, Quinazolines, biology.protein
Abstract: International audience; Hepatitis C virus (HCV) is a major cause of liver disease, but therapeutic options are limited and there are no prevention strategies. Viral entry is the first step of infection and requires the cooperative interaction of several host cell factors. Using a functional RNAi kinase screen, we identified epidermal growth factor receptor and ephrin receptor A2 as host cofactors for HCV entry. Blocking receptor kinase activity by approved inhibitors broadly impaired infection by all major HCV genotypes and viral escape variants in cell culture and in a human liver chimeric mouse model in vivo. The identified receptor tyrosine kinases (RTKs) mediate HCV entry by regulating CD81-claudin-1 co-receptor associations and viral glycoprotein-dependent membrane fusion. These results identify RTKs as previously unknown HCV entry cofactors and show that tyrosine kinase inhibitors have substantial antiviral activity. Inhibition of RTK function may constitute a new approach for prevention and treatment of HCV infection.
Published: 2011

34. Étude du leucotropisme du virus de l’hépatite C par analyse des quasi-espèces virales dans le contexte de la transplantation hépatique

Author: Carole Meyer, Catherine A. Royer, Eric Soulier, Bernard Ellero, Françoise Stoll-Keller, Samira Fafi-Kremer, Michel Doffoel, T. Weitten, N. Brignon, F. Schramm, Thomas Baumert, Evelyne Schvoerer, Philippe Wolf, Marie-Lorraine Woehl-Jaegle, R. Moenne-Loccoz, J.-P. Gut, Laboratoire de Virologie [Strasbourg], Centre de résonance magnétique biologique et médicale (CRMBM), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Service d'hépato-gastroentérologie, CHU Strasbourg-Hopital Civil, Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0303 health sciences, Hepatitis C virus, medicine.medical_treatment, General Medicine, Hepatitis C, Liver transplantation, Biology, Compartmentalization (psychology), medicine.disease, medicine.disease_cause, Peripheral blood mononuclear cell, Viral infection, Virology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, medicine, 030211 gastroenterology & hepatology, Transplant patient, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: Besides hepatocytes, representing the main replication site of hepatitis C virus, peripheral blood mononuclear cells also represent a crucial target for viral infection. Hepatitis C virus compartmentalization (i.e., non-random distribution) of viral variants between plasma and peripheral blood mononuclear cells, more frequently observed in liver transplant patients compared to non-transplanted patients, makes liver transplantation an interesting model for the analysis of hepatitis C leukotropism. This article aims to present, firstly, in clinical and biological features arguing favour of hepatitis C virus infection leukotropism and, secondly, to review current knowledge about compartmentalization between plasma and peripheral blood mononuclear cells, especially in the liver transplantation setting.
Published: 2008

35. Corrigendum to 'Synthesis of unnatural 2- and 3-deoxyfuranose analogues' [Tetrahedron Lett. 55 (2014) 3706–3708]

Author: Dominique Surleraux, David Virieux, Arie Van der Lee, Daniel Da Costa, Gilles Gosselin, Jean-Noël Volle, Bénédicte Dayde, Amadou Tidjani Ilagouma, Claire Pierra, Jean-Luc Pirat, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), Idenix Pharmaceuticals, Medicinal Chemistry Laboratory-Cap Gamma, Laboratoire Coopératif Idénix, Université Montpellier 2 - Sciences et Techniques (UM2), Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Departement de Chimie, Université Abdou Moumouni [Niamey], Institut Européen des membranes (IEM), and Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)
Subjects: 010405 organic chemistry, Stereochemistry, Chemistry, Organic Chemistry, Drug Discovery, Tetrahedron, [CHIM]Chemical Sciences, 010402 general chemistry, 01 natural sciences, Biochemistry, ComputingMilieux_MISCELLANEOUS, 0104 chemical sciences
Abstract: International audience
Published: 2015

36. Ledipasvir-sofosbuvir with or without ribavirin to treat patients with HCV genotype 1 infection and cirrhosis non-responsive to previous protease-inhibitor therapy: a randomised, double-blind, phase 2 trial (SIRIUS)

Author: John G. McHutchison, Stanislas Pol, Dominique Larrey, Albert Tran, Sophie Metivier, Patrick Marcellin, Victor de Ledinghen, Lawrence Serfaty, François Habersetzer, Vlad Ratziu, Phillip S. Pang, William T. Symonds, Jean-Didier Grangé, Robert H. Hyland, Laurent Alric, Vincent Leroy, Véronique Loustaud-Ratti, Jean-Pierre Bronowicki, Deyuan Jiang, Philippe Mathurin, Dominique Guyader, Marc Bourlière, Fabien Zoulim, Christophe Hézode, Armand Abergel, G. Mani Subramanian, Brian P. Doehle, Service d'hépato-gastro-entérologie, Assistance Publique - Hôpitaux de Marseille (APHM), Service d'Hépato-gastro-entérologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie du cancer du foie, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM U955, équipe 18, Service d'hépato-gastro-entérologie [APHP Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Hépato-gastroentérologie, Hôpital Huriez-Université de Lille, Cellules souches normales et cancéreuses, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Division of Gastroenterology, Duke Clinical Research Institute-Duke University Medical Center, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Gastro-entérologie - Hépatologie [Purpan], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Centre Hospitalier Universitaire Estaing, Service d'hépatologie médicale [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut Mondor de Recherche Biomédicale (IMRB), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Inserm U1065, Centre Méditerranéen de Médecine Moléculaire, Centre de Recherche Saint-Antoine (UMRS893), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Gilead Sciences, Inc. [Foster City, CA, USA], Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UMR INSERM 1092, Université of Limoges, CHU Saint-Antoine [AP-HP], Pôle Maladies de l'appareil digestif [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalo-Universitaire de Grenoble (CHU de Grenoble), CHU Grenoble, CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance Publique - Hôpitaux de Marseille ( APHM ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Nutrition-Génétique et Exposition aux Risques Environnementaux ( NGERE ), Université de Lorraine ( UL ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10, Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Montpellier 1 ( UM1 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Pharmacochimie et Pharmacologie Pour le Développement ( PHARMA-DEV ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique ( CNRS ), Centre de recherche sur l'Inflammation ( CRI ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and CHU Cochin [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP)
Subjects: Liver Cirrhosis, Male, Cirrhosis, Sofosbuvir, Benzimidazoles / therapeutic use, [SDV]Life Sciences [q-bio], Hepacivirus, Gastroenterology, RNA Viral / blood, Placebos, chemistry.chemical_compound, Pegylated interferon, Hepatitis C Chronic / virology, Placebos / administration & dosage, Fluorenes / therapeutic use, virus diseases, Hepatitis C, Middle Aged, Viral Load, 3. Good health, Infectious Diseases, Treatment Outcome, RNA, Viral, Female, France, Uridine Monophosphate, Hepacivirus / genetics, medicine.drug, Ledipasvir, Adult, medicine.medical_specialty, Ribavirin / therapeutic use, Adolescent, Genotype, Antiviral Agents / therapeutic use, Hepatitis C Chronic / drug therapy, Liver Cirrhosis / drug therapy, Placebo, Antiviral Agents, Liver Cirrhosis / virology, Young Adult, Double-Blind Method, Hepatitis C Chronic / complications, Internal medicine, Ribavirin, medicine, Humans, Uridine Monophosphate / therapeutic use, Hepacivirus / isolation & purification, Aged, Fluorenes, Uridine Monophosphate / analogs & derivatives, [ SDV ] Life Sciences [q-bio], business.industry, Hepacivirus / classification, Hepatitis C, Chronic, medicine.disease, digestive system diseases, Surgery, Regimen, chemistry, Benzimidazoles, business
Abstract: Summary Background Patients with cirrhosis resulting from chronic hepatitis C virus (HCV) infection are at risk of life-threatening complications, but consistently achieve lower sustained virological response (SVR) than patients without cirrhosis, especially if treatment has previously failed. We assessed the efficacy and safety of the NS5A inhibitor ledipasvir and the nucleotide polymerase inhibitor sofosbuvir, with and without ribavirin. Methods In this multicentre, double-blind trial, between Oct 21, 2013, and Oct 30, 2014, we enrolled patients with HCV genotype 1 and compensated cirrhosis who had not achieved SVR after successive treatments with pegylated interferon and protease-inhibitor regimens at 20 sites in France. With a computer-generated randomisation sequence, patients were assigned in a 1:1 ratio to receive placebo matched in appearance to study drugs for 12 weeks followed by once daily combination fixed-dose tablets of 90 mg ledipasvir and 400 mg sofosbuvir plus weight-based ribavirin for 12 weeks, or ledipasvir-sofosbuvir plus placebo once daily for 24 weeks. The primary endpoint was SVR 12 weeks after the end of treatment (SVR12), for which 95% CIs were calculated with the Clopper-Pearson method. This study is registered with ClinicalTrials.gov, number NCT01965535. Findings Of 172 patients screened, 155 entered randomisation, 77 were assigned to receive ledipasvir-sofosbuvir plus ribavirin and 78 ledipasvir-sofosbuvir. 114 (74%) were men, 151 (97%), were white, 98 (63%) had HCV genotype 1a, and 145 (94%) had non-CC IL28B alleles. SVR12 rates were 96% (95% CI 89–99) for patients in the ledipasvir-sofosbuvir plus ribavirin group and 97% (91–100) in the ledipasvir-sofosbuvir group. One patient discontinued treatment because of adverse events while receiving only placebo. The most frequent adverse events were asthenia and headache, pruritus, and fatigue. Interpretation Ledipasvir-sofosbuvir plus ribavirin for 12 weeks and ledipasvir-sofosbuvir for 24 weeks provided similarly high SVR12 rates in previous non-responders with HCV genotype 1 and compensated cirrhosis. The shorter regimen, when given with ribavirin, might, therefore, be useful to treat treatment-experienced patients with cirrhosis if longer-term treatment is not possible. Funding Gilead Sciences.
Published: 2015

37. Antiretroviral-naive and -treated HIV-1 patients can harbour more resistant viruses in CSF than in plasma

Author: Soulié, Cathia, Descamps, Diane, Ronique Schneider, Vé, Trabaud, Mary-Anne, Morand-Joubert, Laurence, Delaugerre, Constance, Montes, Brigitte, Barin, Francis, Ferré, Virginie, Maillard, Anne, Vallet, Sophie, Roussel, Catherine, Assoumou, Lambert, Calvez, Vincent, Flandre, Philippe, Ve, Anne-Geneviè, Jeulin, H., Guigon, A., Lagier, E., Le Guillou, H., Alloui, C., Bettinger, D., Pallier, C., Fleury, H., Reigadas, S., Bellecave, P., Recordon-Pinson, P., Payan, C., Vabret, A., Henquell, C., Mirand, A., Bouvier-Alias, M., de Rougemont, Alexis, dos Santos, G., Morand, P., Signori-Schmuck, A., Bocket, L., Rogez, S., Andre, P., Tardy, J., Tamalet, C., Delamare, C., Schvoerer, E., André-Garnier, E., Cottalorda, J., Guinard, J., Guiguon, A., Brun-Vezinet, F., Charpentier, C., Visseaux, B., Peytavin, G., Krivine, A., Si-Mohamed, A., Avettand-Fenoel, V., Marcelin, A.-G., Lambert-Niclot, S., Wirden, M., Chaix, M., Amiel, C., Schneider, V., Giraudeau, G., Brodard, V., Plantier, J., Chaplain, C., Bourlet, T., Fafi-Kremer, S., Stoll-Keller, F., Schmitt, M., Barth, H., Yerly, S., Poggi, C., Izopet, Jacques, Raymond, S., Chaillon, A., Marque-Juillet, S., Roque-Afonso, A., Haim-Boukobza, S., Grude, Maxime, Costagliola, D., Allegre, T., Schmit, J., Chennebault, J., Bouchaud, O., Magy-Bertrand, N., Delfraissy, J., Dupon, M., Morlat, P., Neau, D., Ansart, S., Jaffuel, S., Verdon, R., Jacomet, C., Levy, Y., Dominguez, S., Chavanet, P., Piroth, L., Cabié, A., Leclercq, P., Ajana, F., Cheret, A., Weinbreck, P., Cotte, L., Poizot-Martin, I., Ravaud, I., Christian, B., Truchetet, F., Grandidier, M., Reynes, J., May, T., Goehringer, F., Raffi, F., Dellamonica, P., Prazuck, T., Hocqueloux, L., Yeni, P., Landman, R., Launay, O., Weiss, L., Viard, J., Katlama, C., Simon, A., Girard, Pascal, Meynard, J., Molina, J., Pialoux, G., Hoen, B., Goeger-Sow, M., Lamaury, I., Beaucaire, G., Jaussaud, R., Rouger, C., Michelet, C., Borsa-Lebas, F., Caron, F., Khuong, M., Lucht, F., Rey, D., Calmy, A., Marchou, B., Gras, G., Greder-Belan, A., Vittecoq, D., Teicher, E., Epidémiologie, stratégies thérapeutiques et virologie cliniques dans l'infection à VIH, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Virologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de bactériologie-virologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Génétique et Ecologie des Virus, Génétique des Virus et Pathogénèse des Maladies Virales, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre national de référence du VIH INSERM U966, Université de Tours (UT), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Pontchaillou [Rennes], Laboratoire de Parasitologie et Mycologiede [CHRU Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de bactériologie-virologie [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Modélisation mathématique, calcul scientifique (MMCS), Institut Camille Jordan [Villeurbanne] (ICJ), École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet [Saint-Étienne] (UJM)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet [Saint-Étienne] (UJM)-Centre National de la Recherche Scientifique (CNRS), Service de Virologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Neuroimagerie cognitive (LCogn), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Microbiologie Fondamentale et Pathogénicité (MFP), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Laboratoire de Virologie Humaine et Moléculaire [Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Faculté de médecine et pharmacie, CHU Clermont-Ferrand, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), UFR des Sciences de Santé (Université de Bourgogne), Université de Bourgogne (UB), Centre National de Référence des virus entériques [CHU de Dijon] (CNR virus entériques), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire de sérologie-virologie (CHU de Dijon), Procédés Alimentaires et Microbiologiques [Dijon] (PAM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université Bourgogne Franche-Comté [COMUE] (UBFC), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Biologie structurale des interactions entre virus et cellule hôte (UVHCI), Université Joseph Fourier - Grenoble 1 (UJF)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Centre National de la Recherche Scientifique (CNRS), CHU Limoges, Laboratoire d'Informatique de Nantes Atlantique (LINA), Mines Nantes (Mines Nantes)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'électronique, optoélectronique et microsystèmes (LEOM), Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, Institut des sciences biologiques (INSB-CNRS)-Institut des sciences biologiques (INSB-CNRS)-Centre National de la Recherche Scientifique (CNRS), Hôtel-Dieu de Nantes, Service de chirurgie pédiatrique [Hôpital Lapeyronie-Arnaud de Villeneuve], Hôpital Lapeyronie [Montpellier] (CHU), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Equipe de Recherche en Physico-Chimie et Biotechnologie (ERPCB), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Interactions et dynamique des environnements de surface (IDES), Université Paris-Sud - Paris 11 (UP11)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Virologie [Strasbourg], Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Environment and Sustainable Development Programme, European Commission - DG Research and Innovation, Centre Hospitalier Intercommunal de Toulon - La Seyne-sur-Mer, Laboratoire de Virologie [Toulouse], CHU Toulouse [Toulouse], Magnétisme et Diffusion Neutronique (MDN), Modélisation et Exploration des Matériaux (MEM), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre Hospitalier du Pays d'Aix, CHU Bordeaux [Bordeaux], Fédération des Maladies Infectieuses [Bordeaux], CHU de Bordeaux Pellegrin [Bordeaux], Service de médecine interne 2 et maladies infectieuses, Unité de Maladies Infectieuses et Tropicales [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Dijon, Département d'infectiologie (CHU de Dijon), Centre d'Investigation Clinique Antilles-Guyane (CIC - Antilles Guyane), Université des Antilles et de la Guyane (UAG)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -CHU de Fort de France-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Bell Labs (BELL), Lucent Technologies, Service des Maladies Infectieuses et Tropicales [CHRU Nancy], Service des maladies infectieuses et tropicales [CHU Nantes], CIC - Biotherapie - AP-HP (cochin - Pasteur), Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Maladies Infectieuses et Tropicales [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut d’Electronique et des Systèmes (IES), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Génétique Cellulaire (LGC), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Service de Médecine interne, Maladies Infectieuses et Immunologie Clinique [Reims], Centre Hospitalier Universitaire de Reims (CHU Reims), Institut d’Électronique, de Microélectronique et de Nanotechnologie - UMR 8520 (IEMN), Centrale Lille-Institut supérieur de l'électronique et du numérique (ISEN)-Université de Valenciennes et du Hainaut-Cambrésis (UVHC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université Polytechnique Hauts-de-France (UPHF), CHU Saint-Etienne, CHU Strasbourg, Geneva University Hospital (HUG), Service de Maladies Infectieuses et Tropicales [CHU Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, CHU Besançon, Université de Franche-Comté (UFC), Microbiologie cellulaire et moléculaire et pathogénicité (MCMP), Laboratoire Universitaire de Biodiversité et Ecologie Microbienne (LUBEM), Université de Brest (UBO), Laboratoire Microorganismes : Génome et Environnement - Clermont Auvergne (LMGE), Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biologie structurale des interactions entre virus et cellule hôte, Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), INSB-INSB-Centre National de la Recherche Scientifique (CNRS), CHU Orléans, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), CHU Pitié-Salpêtrière [APHP], Service de Virologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Service de microbiologie [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), University of Applied Sciences Kaiserslautern, Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Hopital l'Archet, Centre d'Information et de Soins de I'Immunodéficience Humaine (CISIH). Hôpital l'Archet 1, Hôpital l'Archet, REseau national d'Investigation clinique en VACcinologie (REIVAC), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP]-Hôtel-Dieu-Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de Gestion des Essais de Produits de Santé (CeNGEPS), Service des maladies infectieuses et tropicales [CHU Pitié-Salpêtrière], Estación Experimental de Pastos y Forrajes 'Indio Hatuey', Société Ragt 2N, Service des maladies infectieuses et tropicales [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), University Hospital and University Jean Monnet, Laboratoire d'Ecologie Alpine (LECA), Centre National de la Recherche Scientifique (CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Université Joseph Fourier - Grenoble 1 (UJF)-Université Grenoble Alpes (UGA), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Camille Jordan (ICJ), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Virologie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT), Laboratoire Chrono-environnement (UMR 6249) (LCE), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Université de Tours, Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Lyon (ECL), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, European Molecular Biology Laboratory [Grenoble] (EMBL)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), CHU de Fort de France-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française]-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles et de la Guyane (UAG), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Centre National de la Recherche Scientifique (CNRS)-Mines Nantes (Mines Nantes)-Université de Nantes (UN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Laboratoire de virologie, Centre National de la Recherche Scientifique (CNRS)-Université Jean Monnet [Saint-Étienne] (UJM)-École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Jean Monnet [Saint-Étienne] (UJM)-École Centrale de Lyon (ECL), Université de Lyon, Université Grenoble Alpes (UGA), Station de recherches sur la vache laitière, Institut National de la Recherche Agronomique (INRA), Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Hôpital Arnaud de Villeneuve, T2, Laboratoire Matériaux Optiques, Photonique et Systèmes (LMOPS), CentraleSupélec-Université de Lorraine (UL)-CentraleSupélec-Université de Lorraine (UL), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Laboratoire Chrono-environnement - UFC (UMR 6249) (LCE), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Institut d’Électronique, de Microélectronique et de Nanotechnologie (IEMN) - UMR 8520 (IEMN), Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Université Polytechnique Hauts-de-France (UPHF)-Ecole Centrale de Lille-Université Polytechnique Hauts-de-France (UPHF)-Institut supérieur de l'électronique et du numérique (ISEN), and de ROUGEMONT, Alexis
Subjects: Male, Drug Resistance, HIV Infections, medicine.disease_cause, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Antiretroviral Therapy, Highly Active, Genotype, Pharmacology (medical), 030212 general & internal medicine, Viral, ComputingMilieux_MISCELLANEOUS, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, ddc:616, 0303 health sciences, Mutation, medicine.diagnostic_test, Proteolytic enzymes, virus diseases, Pharmacology and Pharmaceutical Sciences, Viral Load, Middle Aged, 3. Good health, ANRS Resistance AC11 Group, Infectious Diseases, Medical Microbiology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, HIV/AIDS, ARV, Female, Infection, Viral load, Microbiology (medical), Adult, Anti-HIV Agents, Antiretroviral Therapy, CSF, Microbial Sensitivity Tests, Biology, [SDV.MP.PRO]Life Sciences [q-bio]/Microbiology and Parasitology/Protistology, Microbiology, Virus, resistance, 03 medical and health sciences, Clinical Research, Drug Resistance, Viral, medicine, Genetics, Humans, Highly Active, Gene, Pharmacology, 030306 microbiology, Lumbar puncture, Neurosciences, HIV, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Reverse transcriptase, Immunology, HIV-1, Antimicrobial Resistance, Nervous System Diseases
Abstract: International audience; Objectives: The neurological disorders in HIV-1-infected patients remain prevalent. The HIV-1 resistance in plasma and CSF was compared in patients with neurological disorders in a multicentre study. Methods: Blood and CSF samples were collected at time of neurological disorders for 244 patients. The viral loads were .50 copies/mL in both compartments and bulk genotypic tests were realized. Results: On 244 patients, 89 and 155 were antiretroviral (ARV) naive and ARV treated, respectively. In ARV-naive patients, detection of mutations in CSF and not in plasma were reported for the reverse transcriptase (RT) gene in 2/89 patients (2.2%) and for the protease gene in 1/89 patients (1.1%). In ARV-treated patients, 19/152 (12.5%) patients had HIV-1 mutations only in the CSF for the RT gene and 30/151 (19.8%) for the protease gene. Two mutations appeared statistically more prevalent in the CSF than in plasma: M41L (P ¼ 0.0455) and T215Y (P ¼0.0455). Conclusions: In most cases, resistance mutations were present and similar in both studied compartments. However, in 3.4% of ARV-naive and 8.8% of ARV-treated patients, the virus was more resistant in CSF than in plasma. These results support the need for genotypic resistance testing when lumbar puncture is performed.
Published: 2015

38. Identification of a duplicated V3 domain in NS5A associated with cirrhosis and hepatocellular carcinoma in HCV-1b patients

Author: Elisabeth André-Garnier, J. B. Bour, Jacques Izopet, Christophe Lemaire, S. Vallet, Adeline Pivert, Arielle R. Rosenberg, Pascale Trimoulet, Christopher Payan, E. Bouthry, Pascal Veillon, Sophie Alain, Dominique Bettinger, P. André, Alexandra Ducancelle, Catherine Gaudy-Graffin, Jean-Michel Pawlotsky, Françoise Stoll-Keller, Odile Petsaris, Cécile Henquell, Yazid Baazia, Bruno Pozzetto, Françoise Lunel-Fabiani, Florence Abravanel, Henia Saoudin, V. Thibault, Anne Signori-Schmuck, Sandrine Bertrais, Gisèle Lagathu, H. Le Guillou-Guillemette, Sylvie Larrat, S. Minjolle-Cha, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), SFR UA 4208 Interactions Cellulaires et Applications Thérapeutiques (ICAT), Université d'Angers (UA), CHU Limoges, Service de virologie [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Laboratoire de Virologie [Toulouse], CHU Toulouse [Toulouse], Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Clermont-Ferrand, Hôtel-Dieu de Nantes, Laboratoire Universitaire de Biodiversité et Ecologie Microbienne (LUBEM), Université de Brest (UBO), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Avicenne, Service de virologie et d'immunologie biologique, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Laboratoire de Bactériologie de l'Hôpital de la Croix-Rousse, Hospices Civils de Lyon (HCL), Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH - U1259 Inserm - CHRU Tours ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Unit for Virus Host-Cell Interactions [Grenoble] (UVHCI), Centre National de la Recherche Scientifique (CNRS)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Université Joseph Fourier - Grenoble 1 (UJF), Biologie structurale des interactions entre virus et cellule hôte (UVHCI), Université Joseph Fourier - Grenoble 1 (UJF)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), CHU Pontchaillou [Rennes], Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Henri Mondor, The authors thank A. Lefebvre, E. Muel, Y. Desille, I. Renard, A. Plages, A. Rodallec and W. Merrouche for their assistance in clinical data recording.Funding: This study was funded by the ANRS (Agence de Nationale de Recherche sur le VIH et les hépatites, appel d’offre Mars 2006)., PRES Université Nantes Angers Le Mans [UNAM], Interactions cellulaires et applications thérapeutiques (ICAT), Université d'Angers (UA) - CHU Angers - CRLCC Paul Papin - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Service de virologie, Université Pierre et Marie Curie - Paris 6 (UPMC) - Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Pitié-Salpêtrière [APHP], Centre de Physiopathologie Toulouse Purpan, Université Paul Sabatier - Toulouse 3 (UPS) - IFR30 - IFR150 - Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Cochin [APHP], Université européenne de Bretagne (UEB) - Université de Bretagne Occidentale (UBO) - IFR148 ScInBioS, Centre Hospitalier Universitaire de Dijon (CHU Dijon), CHU Bordeaux [Bordeaux] - Groupe hospitalier Pellegrin, Hospices Civils de Lyon, Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH), Institut National de la Santé et de la Recherche Médicale (INSERM) - Université François Rabelais - Tours - CHRU Tours, CHU Besançon, Université de Franche-Comté (UFC), Laboratoire de biologie structurale des interactions entre virus et cellule hôte, Université Joseph Fourier - Grenoble 1 (UJF) - Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg - Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), European Molecular Biology Laboratory [Grenoble] (EMBL)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Laboratoire Virologie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), CHU Henri Mondor [Créteil], and Jonchère, Laurent
Subjects: Adult, Liver Cirrhosis, Male, hepatitis C virus, Cirrhosis, Carcinoma, Hepatocellular, Hepatitis C virus, [SDV]Life Sciences [q-bio], Viral quasispecies, Hepacivirus, Biology, Viral Nonstructural Proteins, medicine.disease_cause, NS5A, Liver disease, Virology, Gene Duplication, Gene duplication, medicine, Prevalence, Humans, Aged, Hepatitis, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Sequence Analysis, RNA, cirrhosis, Liver Neoplasms, Hepatitis C, hepatocellular carcinoma, Hepatitis C, Chronic, Middle Aged, medicine.disease, digestive system diseases, 3. Good health, Protein Structure, Tertiary, [SDV] Life Sciences [q-bio], Mutagenesis, Insertional, Infectious Diseases, Cross-Sectional Studies, Hepatocellular carcinoma, RNA, Viral, Female, V3 domain, France, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Background The NS5A protein of the hepatitis C virus has been shown to be involved in the development of hepatocellular carcinoma. Objectives In a French multicenter study, we investigated the clinical and epidemiological features of a new HCV genotype 1b strain bearing a wide insertion into the V3 domain. Study Design We studied NS5A gene sequences in 821 French patients infected with genotype 1b HCV. Results We identified an uncharacterized V3 insertion without ORF disruption in 3.05% of the HCV sequences. The insertion comprised 31 amino-acids for the majority of patients; 3 patients had 27 amino-acids insertions and 1 had a 12 amino-acids insertion. Sequence identity between the 31 amino-acids insertions and the V3 domain ranged from 48 to 96% with E-values above 4e-5, thus illustrating sequence homology and a partial gene duplication event that to our knowledge has never been reported in HCV. Moreover we showed the presence of the duplication at the time of infection and its persistence at least during 12 years in the entire quasispecies. No association was found with extrahepatic diseases. Conversely, patients with cirrhosis were two times more likely to have HCV with this genetic characteristic (p=0.04). Moreover, its prevalence increased with liver disease severity (from 3.0% in patients without cirrhosis to 9.4% in patients with both cirrhosis and HCC, p for trend=0.045). Conclusions We identified a duplicated V3 domain in the HCV-1b NS5A protein for the first time. The duplication may be associated with unfavorable evolution of liver disease including a possible involvement in liver carcinogenesis
Published: 2015

39. Cholesterol uptake and hepatitis C virus entry

Author: Joachim Lupberger, Daniel J. Felmlee, Thomas F. Baumert, Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hépato-gastroentérologie, Hôpitaux Universitaires de Strasbourg-Nouvel Hôpital Civil, and Baumert, Thomas F.
Subjects: medicine.medical_specialty, Hepatitis C virus, Entry, NPC1L1, medicine.disease_cause, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Ezetimibe, Viral entry, In vivo, Interferon, Internal medicine, medicine, Gene silencing, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Hepatology, business.industry, virus diseases, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Virology, digestive system diseases, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, Cholesterol, HCV, 030211 gastroenterology & hepatology, business, medicine.drug
Abstract: Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. With 170 million individuals infected and current interferon-based treatment having toxic side effects and marginal efficacy, more effective antivirals are crucially needed. Although HCV protease inhibitors were just approved by the US Food and Drug Administration (FDA), optimal HCV therapy, analogous to HIV therapy, will probably require a combination of antivirals targeting multiple aspects of the viral lifecycle. Viral entry represents a potential multifaceted target for antiviral intervention; however, to date, FDA-approved inhibitors of HCV cell entry are unavailable. Here we show that the cellular Niemann–Pick C1-like 1 (NPC1L1) cholesterol uptake receptor is an HCV entry factor amendable to therapeutic intervention. Specifically, NPC1L1 expression is necessary for HCV infection, as silencing or antibody-mediated blocking of NPC1L1 impairs cell culture-derived HCV (HCVcc) infection initiation. In addition, the clinically available FDA-approved NPC1L1 antagonist ezetimibe potently blocks HCV uptake in vitro via a virion cholesterol-dependent step before virion–cell membrane fusion. Moreover, ezetimibe inhibits infection by all major HCV genotypes in vitro and in vivo delays the establishment of HCV genotype 1b infection in mice with human liver grafts. Thus, Journal of Hepatology 20
Published: 2012
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40. Performance of Pyridylthiourea-Polyethylenimine Polyplex for siRNA-Mediated Liver Cancer Therapy in Cell Monolayer, Spheroid, and Tumor Xenograft Models

Author: Francine Gossé, Mathieu Gonçalves, Florent Meyer, Benoît Frisch, Cendrine Seguin, Guy Zuber, Jean Baptiste Gossart, Etienne Pascal, Emilie Heuillard, Eric Robinet, Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Conception et application de molécules bioactives (CAMB), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), and Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Small interfering RNA, [SDV.CAN]Life Sciences [q-bio]/Cancer, 02 engineering and technology, delivery system, Biology, liver cancer, polo‐like kinase, 03 medical and health sciences, chemistry.chemical_compound, In vivo, RNA interference, medicine, ComputingMilieux_MISCELLANEOUS, Gene knockdown, Polyethylenimine, Full Paper, Spheroid, Cancer, Sciences du Vivant [q-bio]/Biotechnologies, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Full Papers, 021001 nanoscience & nanotechnology, medicine.disease, Molecular biology, polyethylenimine, 3. Good health, [CHIM.POLY]Chemical Sciences/Polymers, 030104 developmental biology, chemistry, Tumor progression, siRNA, Cancer research, 0210 nano-technology
Abstract: Medical application of siRNAs relies on methods for delivering nucleic acids into the cytosol. Synthetic carriers, which assemble with nucleic acids into delivery systems, show promises for cancer therapy but efficiency remains to be improved. In here, the effectiveness of pyridylthiourea‐polyethylenimine (πPEI), a siRNA carrier that favors both polyplex disassembly and endosome rupture upon sensing the acidic endosomal environment, in 3 experimental models of hepatocellular cancer is tested. The πPEI‐assisted delivery of a siRNA targeting the polo‐like kinase 1 into Huh‐7 monolayer produces a 90% cell death via a demonstrated RNA interference mechanism. Incubation of polyplex with Huh‐7 spheroids leads to siRNA delivery into the superficial first cell layer and a 60% reduction in spheroid growth compared to untreated controls. Administration of polyplexes into mice bearing subcutaneous implanted Huh‐7Luc tumors results in a reduced tumor progression, similar to the one observed in the spheroid model. Altogether, these results support the in vivo use of synthetic and dedicated polymers for increasing siRNA‐mediated gene knockdown, and their clinical promise in cancer therapeutics.
Published: 2017

41. Opening the door for hepatitis C virus infection in genetically humanized mice

Author: Thomas F. Baumert, Daniel Da Costa, Mirjam B. Zeisel, Zeisel, Mirjam, Interaction virus-hôte et maladies du foie, and Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0303 health sciences, Hepatology, Hepatitis C virus, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Biology, medicine.disease_cause, Virology, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Immunology, medicine, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: International audience
Published: 2011

42. Influences non conscientes sur des processus mentaux complexes : initiation de stratégies et sentiment de contrôle

Author: Weibel, Sébastien, STAR, ABES, Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Strasbourg, and Anne Giersch
Subjects: Consciousness, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Cognitive control, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Schizophrenia, Contrôle cognitif, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Agentivity, Agentivité, Schizophrénie, Subliminal, Conscience, [SDV.NEU.SC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences
Abstract: Do unconscious stimuli modify processes that are typically associated with consciousness? This question is of particular interest in schizophrenia in which there is both impairments of implicit processes and abnormalities of conscious processes. For instance patients have difficulties to initiate a strategy or to feel in control of their actions. For this purpose, we wanted to know to what extent the choice of a task set or the feeling of control over the action could be influenced by unconscious cues. We conducted two studies in healthy subjects showing that unconscious stimuli can influence the preparation of a task set. However, we have shown that there are limitations to these unconscious influences: the processing of unconscious stimuli must be uninterrupted for some time, and it is modulated by attentional mechanisms. Our third study analyzed the effect of subliminal distortions of the haptic feedback (tactile and kinesthetic) on motor adaptation and on the conscious sense of control over the action. We have shown that the feeling of control was modulated by subliminal distortions of the haptic feedback. Unconscious influences have an impact on conscious processes, but in limited and controlled circumstances., Est-ce que des stimuli non conscients peuvent modifier des processus classiquement considérés comme conscients ? Cette question est d’un intérêt particulier dans la schizophrénie où il existe à la fois des anomalies de processus implicites et des anomalies de processus conscients, comme par exemple, initier une stratégie ou se sentir en contrôle de son action. Pour réaliser des études chez les patients, nous devions savoir dans quelle mesure le choix d’une stratégie ou le sentiment de contrôler son action sont soumis à des influences non conscientes. Nous avons réalisé deux études chez le sujet sain montrant qu’un stimulus non conscient peut influencer la préparation d’une stratégie. Cependant, il existe des limites à ces influences non conscientes : le traitement du stimulus non conscient ne doit pas être interrompu trop tôt, et des filtres attentionnels le modulent. Notre troisième étude a analysé l’effet de distorsions subliminales du retour haptique (tactile et kinesthésique) sur l’adaptation motrice et sur le sentiment conscient de contrôler son action. Nous avons montré que le sentiment de contrôler l’action était modulé par des distorsions du retour haptique, même quand celui-ci est subliminaire. Les influences non conscientes ont un impact sur les processus habituellement conscients, dans des circonstances limitées et contrôlées.
Published: 2014

43. Influenza outbreaks management in a French psychiatric hospital from 2004 to 2012

Author: Pascale Minery, Françoise Stoll-Keller, D. Gunther, Daniel Talon, Xavier Bertrand, Anne Mosnier, Philippe Gaspard, Sabrina Larocca, Céline Lochert, Réseau des Groupes Régionaux d'Observation de la Grippe ( GROG ), Coordination nationale, Interaction virus-hôte et maladies du foie, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire Chrono-environnement ( LCE ), Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ) -Centre National de la Recherche Scientifique ( CNRS ), Hôpital Jean Minjoz, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Réseau des Groupes Régionaux d'Observation de la Grippe (GROG), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), and Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)
Subjects: Adult, Hospitals, Psychiatric, medicine.medical_specialty, Influenza epidemics, Antiviral Agents, Disease Outbreaks, 03 medical and health sciences, 0302 clinical medicine, Protective Clothing, [ SDV.MP ] Life Sciences [q-bio]/Microbiology and Parasitology, Influenza, Human, medicine, Psychiatric hospital, Infection control, Humans, 030212 general & internal medicine, Intensive care medicine, Aged, Geriatrics, 0303 health sciences, Cross Infection, Infection Control, 030306 microbiology, business.industry, Masks, Outbreak, virus diseases, Middle Aged, Mental health, 3. Good health, Psychiatry and Mental health, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Curative treatment, Influenza Vaccines, Chemoprophylaxis, France, business
Abstract: International audience; OBJECTIVE: Influenza epidemics can have consequences in terms of morbidity and mortality for the patients. This work assesses influenza outbreaks in order to validate and optimize alert and control measures in a psychiatric hospital. METHOD: The prospective monitoring of influenza episodes was conducted for 8 years in 19 units of a mental health hospital. Rapid influenza diagnostic tests were used. The study of the episodes with confirmed influenza cases was carried out. RESULTS: Influenza monitoring and alert were essential with information and laboratory-confirmed cases. Influenza was common with a total of 20 episodes for the studied period. A maximum of 25% (5/20) of the units were affected in 2008-2009. Rapid influenza diagnostic tests allowed a quick identification with an average time of 1.5 days. Mainly, control measures limited the spread of the influenza virus in units with patient not at high risk of complications. On the other hand, antiviral curative treatment and chemoprophylaxis are essential in units with patients at high risk of complications. CONCLUSION: In a psychiatric hospital, influenza management has to take into account the exposed patient's risks for influenza complications and to adapt the strategy according to the risks identified.
Published: 2014

44. Epstein-Barr virus infection and clinical outcome in breast cancer patients correlate with immune cell TNF-α/IFN-γ response

Author: Catherine Fallecker, Samira Fafi-Kremer, Sofia Franco, Carlos Freire de Oliveira, Artur Paiva, Gina Marrão, Emmanuel Drouet, Mohammed Habib, Teresa Simões Silva, Patrice Morand, Dominique J. Bicout, Unit for Virus Host-Cell Interactions [Grenoble] (UVHCI), Centre National de la Recherche Scientifique (CNRS)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Université Joseph Fourier - Grenoble 1 (UJF), Instituto Português de Sangue e da Transplantação [Coimbra] (IPST), Laboratoire d'informatique Algorithmique : Fondements et Applications (LIAFA), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Networks, Graphs and Algorithms (GANG), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Inria Paris-Rocquencourt, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Instituto Superior de Engenharia de Coimbra, Universidade de Trás-os-Montes e Alto Douro (UTAD), Environnement et Prédiction de la Santé des Populations (TIMC-IMAG-EPSP), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Laboratoire de l'Accélérateur Linéaire (LAL), Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Paris-Sud - Paris 11 (UP11), Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Departamento de Patologia [Coimbra], Centro Hospitalar e Universitário [Coimbra], Departamento de Ginecologia [Coimbra], Universidade de Coimbra [Coimbra]-Centro Hospitalar e Universitário [Coimbra], Université Joseph Fourier - Grenoble 1 (UJF)-European Molecular Biology Laboratory [Grenoble] (EMBL)-Centre National de la Recherche Scientifique (CNRS), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), and Université Paris-Sud - Paris 11 (UP11)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Cancer Research, Epstein-Barr Virus Infections, Herpesvirus 4, Human, Survival, T-Lymphocytes, Breast Neoplasms, Peripheral blood mononuclear cell, Virus, Interferon-gamma, Immune system, Breast cancer, Immunocompetent cells, EBV, Genetics, Medicine, Humans, Viral load, Epstein–Barr virus infection, IFN-γ, Survival analysis, Aged, Aged, 80 and over, Tumor, biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], business.industry, Tumor Necrosis Factor-alpha, Middle Aged, medicine.disease, Survival Analysis, 3. Good health, Killer Cells, Natural, Oncology, Multivariate analysis, TNF-α, Immunology, biology.protein, Tumor necrosis factor alpha, Female, Antibody, business, Research Article, ZEBRA
Abstract: Background For nearly two decades now, various studies have reported detecting the Epstein-Barr virus (EBV) in breast cancer (BC) cases. Yet the results are unconvincing, and their interpretation has remained a matter of debate. We have now presented prospective data on the effect of EBV infection combined with survival in patients enrolled in a prospective study. Methods We assessed 85 BC patients over an 87-month follow-up period to determine whether EBV infection, evaluated by qPCR in both peripheral blood mononuclear cells (PBMCs) and tumor biopsies, interacted with host cell components that modulate the evolution parameters of BC. We also examined the EBV replicating form by the titration of serum anti-ZEBRA antibodies. Immunological studies were performed on a series of 35 patients randomly selected from the second half of the survey, involving IFN-γ and TNF-α intracellular immunostaining tests performed via flow cytometry analysis in peripheral NK and T cells, in parallel with EBV signature. The effect of the EBV load in the blood or tumor tissue on patient survival was analyzed using univariate and multivariate analyses, combined with an analysis of covariance. Results Our study represents the first ever report of the impact of EBV on the clinical outcome of BC patients, regardless of tumor histology or treatment regimen. No correlation was found between: (i) EBV detection in tumor or PBMCs and tumor characteristics; (ii) EBV and other prognostic factors. Notably, patients exhibiting anti-ZEBRA antibodies at high titers experienced poorer overall survival (p = 0.002). Those who recovered from their disease were found to have a measurable EBV DNA load, together with a high frequency of IFN-γ and TNF-α producing PBMCs (p = 0.04), which indicates the existence of a Th1-type polarized immune response in both the tumor and its surrounding tissue. Conclusions The replicative form of EBV, as investigated using anti-ZEBRA titers, correlated with poorer outcomes, whereas the latent form of the virus that was measured and quantified using the EBV tumor DNA conferred a survival advantage to BC patients, which could occur through the activation of non-specific anti-tumoral immune responses. Electronic supplementary material The online version of this article (doi:10.1186/1471-2407-14-665) contains supplementary material, which is available to authorized users.
Published: 2013

45. Développement de nouveaux nanovecteurs pour les thérapies anti-HCV/HCC

Author: Alles, Roxane, Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Strasbourg, Thomas Baumert, and Joëlle Ogier
Subjects: [SDV.SA]Life Sciences [q-bio]/Agricultural sciences, Calcium phosphate, SiRNA, HCV, Nanoparticules, Nanoparticles, HCC, Phosphate de calcium, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, PEI
Abstract: This work concerns the development of a nanoparticle vector system for RNA interference,constituting a new therapeutic option applicable to viral and tumor pathologies,and possibly complementary to existing treatments.siRNA vectorisation is here based on multi layer coating of alcium phosphate nanoparticles,the multi layer being constituted of alternate coatings of modified PEI and siRNA.This system triggers a better transfection efficiency of target cells than classic techniques,as well as a functional persistence up to 9 days in vitro.RNA interference results using CPnp allowed inhibition of hepatitis C virus infection up to 99.95%,of intrinsic protein expression up to 90.5%,and of cell growth in a 3 D model mimicking an hepatic tumor up to 46.5%.These nanoparticles could be of major interest,by offering a long term action,and resolving most of the issues found in the use of siRNA in therapy.; Ce travail concerne le développement d’un système de vectorisation nanoparticulaire pour l’interférence ARN, constituant une nouvelle proposition thérapeutique applicable à des pathologies virales ou tumorales, et possiblement complémentaire aux traitements existants. La vectorisation de siRNA est ici basée sur l’enrobage multicouche de nanoparticules de phosphate de calcium, la multicouche étant constituée de dépôts alternés de PEI modifié et de siRNA. Ce système permet d’obtenir une efficacité de transfection des cellulaires cibles supérieure à celle des procédés conventionnels et une rémanence fonctionnelle in vitro jusqu’à neuf jours. Les résultats d’interférence ARN obtenus ont permis notamment d’inhiber l’infection par le virus de l’hépatite C jusqu’à 99,95%, l’inhibition de l’expression d’une protéine intrinsèque jusqu’à90,5%, et le ralentissement de la croissance cellulaire dans un modèle 3D mimant une tumeur hépatique jusqu’à 46,5%. Ces nanoparticules pourraient présenter un intérêt majeur, en offrant une action à long terme et en résolvant la plupart des difficultés rencontrées en utilisant des siRNA en thérapie.
Published: 2013

46. Etude du transfert du VIH-1 des cellules présentatrices d'antigènes aux lymphocytes T CD4 primaires et inhibition par les anticorps neutralisants

Author: Proust, Alizé, Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Strasbourg, Christiane Moog, and STAR, ABES
Subjects: [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Antigen-presenting cells, HIV-1, Cellules présentatrices d'antigènes, Anticorps neutralisants, Neutralizing antibodies, VIH-1, Cell-to-cell transfer, Transfert de cellule-à-cellule, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Antigen-presenting cells (APCs) present at mucosal sites are among the first HIV-1 target cells and contribute to the spread of infection. During my thesis, I studied HIV transfer from macrophages (Mφ) and dendritic cells (DCs) to CD4-T lymphocytes. I showed that APCs were able to efficiently transfer HIV particles to lymphocytes, but through different mechanisms: Mφ rapidlytransferred HIV by direct trans-transfer, whereas DCs were mainly implicated in cistransfer (after production of de novo HIV). Moreover, I have demonstrated that these two modes of transfer were inhibited by neutralizing antibodies (NAb) in both type ofcocultures. Very interestingly, I showed that anti-gp120 NAb inhibit more efficiently HIV transfer in Mφ/T than in DCs/T cocultures and T cells infection by free viral particles. These findings highlight the major contributions of various mucosal target cells in HIV transfer and demonstrate the potent role of NAb on inhibition of cell-to-cell transfer., Les cellules présentatrices d'antigènes (APCs) présentes dans les muqueuses comptent parmi les première cibles du VIH-1 et participent à sa dissémination dans l'organisme. Durant ma thèse, j'ai étudié le transfert du VIH des macrophages (Mφ) et des cellules dendritiques (DCs) aux lymphocytes T. J'ai montré que ces APCs transfèrent efficacement le virus aux lymphocytes par le biais de différents mécanismes: transfert direct en trans dans les coculture Mφ/T, et transfert en cis (suite à la production de nouveaux virions) dans les DCs/T. Ces deux modes de transfert sont inhibés par les anticorps neutralisants (AcN). De manière intéressante, certains AcN anti-gp120 inhibaient plus efficacement le transfert du VIH dans les cocultures Mφ/T que dans les cocultures DCs/T et l'infection des cellules T par le virus libre. Ces résultats suggèrent que les APCs participent activement au transfert et à la dissémination du VIH et que les AcN sont capable d'inhiber ces différents modes de transfert.
Published: 2013

47. Hepatitis C Virus Envelope Glycoprotein Signatures Are Associated With Treatment Failure and Modulation of Viral Entry and Neutralization

Author: Mirjam B. Zeisel, François Habersetzer, John E. Tavis, Samira Fafi-Kremer, John M. Murray, Aurélie Velay, Anne-Claire Erba, Jean-Pierre Gut, Isabel Fofana, Evelyne Schvoerer, Rémy Moenne-Loccoz, Maureen J. Donlin, Marine Turek, Françoise Stoll-Keller, Michel Doffoel, Thomas F. Baumert, Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d’Hépatogastroentérologie, NHC, CHU de Strasbourg, Virology Laboratory, General Hospital Papageorgiou, Interactions Virus-Hôte et Maladies Hépatiques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Virologie, Service d'hépato-gastroentérologie, CHU Strasbourg-Hopital Civil, and SCHVOERER, Evelyne
Subjects: Male, Hepacivirus, Viral transformation, Antibodies, Viral, medicine.disease_cause, 0302 clinical medicine, Viral Envelope Proteins, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Immunology and Allergy, Treatment Failure, ComputingMilieux_MISCELLANEOUS, chemistry.chemical_classification, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 0303 health sciences, biology, Middle Aged, Hepatitis C, 3. Good health, Infectious Diseases, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, 030211 gastroenterology & hepatology, Adult, Genotype, Hepatitis C virus, Antiviral Agents, Structure-Activity Relationship, 03 medical and health sciences, Neutralization Tests, Viral entry, Ribavirin, medicine, Humans, Immune Evasion, 030304 developmental biology, Computational Biology, Virus Internalization, biology.organism_classification, Antibodies, Neutralizing, Herpesvirus glycoprotein B, Virology, NS2-3 protease, HEK293 Cells, chemistry, Mutation, Immunology, Mutagenesis, Site-Directed, Glycoprotein, CD81
Abstract: BACKGROUND: A major challenge for antiviral treatment of hepatitis C virus (HCV) infection is viral resistance, potentially resulting from the high variability of HCV envelope glycoproteins and subsequent selection of strains with enhanced infectivity and/or immune escape. METHODS: We used a bioinformatics and functional approach to investigate whether E1/E2 envelope glycoprotein structure and function were associated with treatment failure in 92 patients infected with HCV genotype 1. RESULTS: Bioinformatics analysis identified 1 sustain virological response (R)-related residue in E1 (219T) and 2 non-SVR (NR)-related molecular signatures in E2 (431A and 642V) in HCV genotype 1a. Two of these positions also appeared in minimal networks separating NR patients from R patients. HCV pseudoparticles (HCVpp) expressing 431A and 642V resulted in a decrease in antibody-mediated neutralization by pretreatment sera. 431A/HCVpp entry into Huh7.5 cells increased with overexpression of CD81 and SR-BI. Moreover, an association of envelope glycoprotein signatures with treatment failure was confirmed in an independent cohort (Virahep-C). CONCLUSIONS: Combined in silico and functional analyses demonstrate that envelope glycoprotein signatures associated with treatment failure result in an alteration of host cell entry factor use and escape from neutralizing antibodies, suggesting that virus-host interactions during viral entry contribute to treatment failure.
Published: 2013

48. Hepatitis C virus entry

Author: Daniel J. Felmlee, Thomas F. Baumert, Mirjam B. Zeisel, Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle Hépato-digestif, Les Hôpitaux Universitaires de Strasbourg (HUS), European Union (ERC-2008- AdG-233130-HEPCENT and INTERREG-IV-2009-FEDER-Hepato-Regio-Net), Laboratoire d'Excellence HEPSYS (Investissement d'Avenir, ANR-10-LAB-28), ANRS (2008/354, 2009/183, 2011/132, 2012/239), Inserm, University of Strasbourg and the Strasbourg University Hospitals, France. DJF is a recipient of an EASL fellowship., European Project: 233130,EC:FP7:ERC,ERC-2008-AdG,HEPCENT(2009), Baumert, Thomas F., and Molecular Analysis of Hepatitis C Virus Neutralization and Entry For the Development of Novel Antiviral Immunopreventive Strategies - HEPCENT - - EC:FP7:ERC2009-04-01 - 2014-03-31 - 233130 - VALID
Subjects: Hepacivirus, Hepatitis C virus, viruses, Virus Attachment, medicine.disease_cause, Antiviral Agents, Virus, Pathogenesis, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Viral life cycle, Animals, Humans, Medicine, 030304 developmental biology, 0303 health sciences, biology, business.industry, virus diseases, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Hepatitis C, Virus Internalization, biology.organism_classification, medicine.disease, Virology, digestive system diseases, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, Host-Pathogen Interactions, Tissue tropism, 030211 gastroenterology & hepatology, business
Abstract: International audience; Hepatitis C virus (HCV) is a hepatotropic virus and a major cause of chronic hepatitis and liver disease worldwide. Initial interactions between HCV virions and hepatocytes are required for productive viral infection and initiation of the viral life cycle. Furthermore, HCV entry contributes to the tissue tropism and species specificity of this virus. The elucidation of these interactions is critical, not only to understand the pathogenesis of HCV infection, but also to design efficient antiviral strategies and vaccines. This review summarizes our current knowledge of the host factors required for the HCV-host interactions during HCV binding and entry, our understanding of the molecular mechanisms underlying HCV entry into target cells, and the relevance of HCV entry for the pathogenesis of liver disease, antiviral therapy, and vaccine development.
Published: 2013

49. Développement de nouveaux nanovecteurs pour les thérapies anti-HCV/HCC

Author: Alles, Roxane, STAR, ABES, Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Strasbourg, Thomas Baumert, and Joëlle Ogier
Subjects: [SDV.SA]Life Sciences [q-bio]/Agricultural sciences, [SDV.SA] Life Sciences [q-bio]/Agricultural sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Nanoparticules, PEI, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Calcium phosphate, SiRNA, HCV, Nanoparticles, HCC, Phosphate de calcium, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: This work concerns the development of a nanoparticle vector system for RNA interference,constituting a new therapeutic option applicable to viral and tumor pathologies,and possibly complementary to existing treatments.siRNA vectorisation is here based on multi layer coating of alcium phosphate nanoparticles,the multi layer being constituted of alternate coatings of modified PEI and siRNA.This system triggers a better transfection efficiency of target cells than classic techniques,as well as a functional persistence up to 9 days in vitro.RNA interference results using CPnp allowed inhibition of hepatitis C virus infection up to 99.95%,of intrinsic protein expression up to 90.5%,and of cell growth in a 3 D model mimicking an hepatic tumor up to 46.5%.These nanoparticles could be of major interest,by offering a long term action,and resolving most of the issues found in the use of siRNA in therapy., Ce travail concerne le développement d’un système de vectorisation nanoparticulaire pour l’interférence ARN, constituant une nouvelle proposition thérapeutique applicable à des pathologies virales ou tumorales, et possiblement complémentaire aux traitements existants. La vectorisation de siRNA est ici basée sur l’enrobage multicouche de nanoparticules de phosphate de calcium, la multicouche étant constituée de dépôts alternés de PEI modifié et de siRNA. Ce système permet d’obtenir une efficacité de transfection des cellulaires cibles supérieure à celle des procédés conventionnels et une rémanence fonctionnelle in vitro jusqu’à neuf jours. Les résultats d’interférence ARN obtenus ont permis notamment d’inhiber l’infection par le virus de l’hépatite C jusqu’à 99,95%, l’inhibition de l’expression d’une protéine intrinsèque jusqu’à90,5%, et le ralentissement de la croissance cellulaire dans un modèle 3D mimant une tumeur hépatique jusqu’à 46,5%. Ces nanoparticules pourraient présenter un intérêt majeur, en offrant une action à long terme et en résolvant la plupart des difficultés rencontrées en utilisant des siRNA en thérapie.
Published: 2013

50. The postbinding activity of scavenger receptor class B type I mediates initiation of hepatitis C virus infection and viral dissemination

Author: Marine Turek, Thomas F. Baumert, John F. Thompson, Viet Loan Dao Thi, Dorothea Bankwitz, Mirjam B. Zeisel, François-Loïc Cosset, Fei Xiao, Isabel Fofana, Johan Neyts, Marlène Dreux, Philippe Bachellier, Maryse Guerin, Fritz Grunert, Leen Delang, Thomas Pietschmann, Muhammad N. Zahid, Baumert, Thomas F., Molecular Analysis of Hepatitis C Virus Neutralization and Entry For the Development of Novel Antiviral Immunopreventive Strategies - HEPCENT - - EC:FP7:ERC2009-04-01 - 2014-03-31 - 233130 - VALID, Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virologie humaine, École normale supérieure - Lyon (ENS Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle des Pathologies Digestives Hépatiques et Transplantation [Hôpital Hautepierre-Strasbourg], Hôpital de Hautepierre [Strasbourg], Aldevron GmbH, Rega Institute for Medical Research [Leuven, België], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Division of Experimental Virology, Centre for Experimental and Clinical Infection Research (TWINCORE), Helmholtz Centre for Infection Research (HZI)-Medizinische Hochschule Hannover (MHH)-Helmholtz Centre for Infection Research (HZI)-Medizinische Hochschule Hannover (MHH), European Union (ERC-2008-AdG-233130-HEPCENT, INTERREG-IV-Rhin Supérieur-FEDER-Hepato-Regio-Net 2009), Laboratoire d'Excellence HEPSYS (Investissement d'Avenir, ANR-10-LAB-28), ANR-05-CEXC-008, ANRS (2008/354, 2009/183, 2011/132), Pro Inno II (KA0690901UL8), Région Alsace, Inserm, University of Strasbourg, and Aldevron Freiburg. The group in Leuven was funded by a grant from the Fund for Scientific Research (FWO) (G.0728.09N) and KULeuven GOA 10/014. M. N. Z. was supported by HEC fellowship., European Project: 233130,EC:FP7:ERC,ERC-2008-AdG,HEPCENT(2009), École normale supérieure de Lyon (ENS de Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM), Les Hôpitaux Universitaires de Strasbourg (HUS), Centre for Experimental and Clinical Infection Research [Hanover] (TWINCORE), Nouvel Hôpital Civil de Strasbourg, and INSERM, U748, Strasbourg, France.
Subjects: CD36 Antigens, [SDV]Life Sciences [q-bio], Hepacivirus, Antigens, CD36, virus entry, medicine.disease_cause, MESH: Lipoproteins, HDL, MESH: Antibodies, Monoclonal, Mice, 0302 clinical medicine, MESH: Animals, MESH: Hepacivirus, Receptor, ComputingMilieux_MISCELLANEOUS, chemistry.chemical_classification, 0303 health sciences, biology, Hepatitis C virus, Antibodies, Monoclonal, scavenger receptor BI, Hepatitis C, antiviral, 3. Good health, 030211 gastroenterology & hepatology, Antibody, MESH: Cholesterol, HDL, Lipoproteins, HDL, MESH: Rats, medicine.drug_class, Monoclonal antibody, viral dissemination, Cell Line, 03 medical and health sciences, Viral entry, medicine, Animals, Humans, Scavenger receptor, MESH: Receptors, Lipoprotein, MESH: Mice, 030304 developmental biology, Receptors, Lipoprotein, MESH: Hepatitis C, MESH: Humans, Hepatology, MESH: Antigens, CD36, Cholesterol, HDL, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Virology, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Rats, MESH: Cell Line, chemistry, Cell culture, biology.protein, Glycoprotein
Abstract: International audience; UNLABELLED: Scavenger receptor class B type I (SR-BI) is a high-density lipoprotein (HDL) receptor highly expressed in the liver and modulating HDL metabolism. Hepatitis C virus (HCV) is able to directly interact with SR-BI and requires this receptor to efficiently enter into hepatocytes to establish productive infection. A complex interplay between lipoproteins, SR-BI and HCV envelope glycoproteins has been reported to take place during this process. SR-BI has been demonstrated to act during binding and postbinding steps of HCV entry. Although the SR-BI determinants involved in HCV binding have been partially characterized, the postbinding function of SR-BI remains largely unknown. To uncover the mechanistic role of SR-BI in viral initiation and dissemination, we generated a novel class of anti-SR-BI monoclonal antibodies that interfere with postbinding steps during the HCV entry process without interfering with HCV particle binding to the target cell surface. Using the novel class of antibodies and cell lines expressing murine and human SR-BI, we demonstrate that the postbinding function of SR-BI is of key impact for both initiation of HCV infection and viral dissemination. Interestingly, this postbinding function of SR-BI appears to be unrelated to HDL interaction but to be directly linked to its lipid transfer function. CONCLUSION: Taken together, our results uncover a crucial role of the SR-BI postbinding function for initiation and maintenance of viral HCV infection that does not require receptor-E2/HDL interactions. The dissection of the molecular mechanisms of SR-BI-mediated HCV entry opens a novel perspective for the design of entry inhibitors interfering specifically with the proviral function of SR-BI.
Published: 2013

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