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1. Humoral immunity to SARS-CoV-2 and seasonal coronaviruses in children and adults in north-eastern France

Author

Tom Woudenberg, Stéphane Pelleau, François Anna, Mikael Attia, Françoise Donnadieu, Alain Gravet, Caroline Lohmann, Hélène Seraphin, Raphaël Guiheneuf, Catherine Delamare, Karl Stefic, Julien Marlet, Etienne Brochot, Sandrine Castelain, Olivier Augereau, Jean Sibilia, François Dubos, Damia Meddour, Christèle Gras-Le Guen, Marianne Coste-Burel, Berthe-Marie Imbert-Marcille, Anne Chauvire-Drouard, Cyril Schweitzer, Amélie Gatin, Sandra Lomazzi, Aline Joulié, Hervé HAAS, Aymeric Cantais, Frederique Bertholon, Marie-France Chinazzo-Vigouroux, Mohamed SI Abdallah, Laurence Arowas, Pierre Charneau, Bruno Hoen, Caroline Demeret, Sylvie Van Der Werf, Arnaud Fontanet, Michael White, Epidémiologie et Analyse des Maladies Infectieuses - Infectious Disease Epidemiology and Analytics, Institut Pasteur [Paris] (IP), Malaria : parasites et hôtes - Malaria : parasites and hosts, Virologie Moléculaire et Vaccinologie / Molecular Virology and Vaccinology, Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre Hospitalier de Mulhouse, site du Hasenrain (Mulhouse), Centre Hospitalier Simone Veil de Beauvais [Beauvais], Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Laboratoire de Virologie [CHU Amiens], CHU Amiens-Picardie, Hôpitaux Civils de Colmar, CHU Strasbourg, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre hospitalier universitaire de Nantes (CHU Nantes), 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), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Pédiatrie [CHRU Nancy], Centre de Ressources Biologiques - [Nancy] (CRB Nancy), Hôpitaux Pédiatriques de Nice Lenval (CHU-Lenval), Centre Hospitalier Universitaire de Nice (CHU Nice), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), agence régionale de santé Hauts-de-France (ARS), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Direction de la recherche médicale de l'Institut Pasteur, Centre National de Référence des virus des infections respiratoires (dont la grippe) - National Reference Center Virus Influenzae [Paris] (CNR - laboratoire coordonnateur), Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology, Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), This work was supported by the « URGENCE COVID-19 » fundraising campaign of Institut Pasteur, by the French Government's Investissement d'Avenir program, Laboratoire d'Excellence Integrative Biology of Emerging Infectious Diseases (Grant No. ANR-10-LABX-62-IBEID), and by the REACTing (Research & Action Emerging Infectious Diseases) and the RECOVER project funded by the European Union's Horizon 2020 research and innovation programme under grant agreement No. 101003589., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), European Project: 101003589, H2020-SC1-PHE-CORONAVIRUS-2020,RECOVER(2020), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Centre National de Référence des virus des infections respiratoires (dont la grippe) - National Reference Center Virus Influenzae [Paris] (CNR), DESSAIVRE, Louise, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, and Rapid European COVID-19 Emergency Response research - RECOVER - - H2020-SC1-PHE-CORONAVIRUS-20202020-02-14 - 2022-02-13 - 101003589 - VALID

Subjects
Male, Medicine (General), viruses, [SDV]Life Sciences [q-bio], Aucun, MESH: Spike Glycoprotein, Coronavirus, Antibodies, Viral, MESH: Cross Reactions, MESH: Aged, 80 and over, Seroepidemiologic Studies, MESH: Child, sero-epidemiology, seasonal coronaviruses, MESH: COVID-19, MESH: Immunity, Humoral, skin and connective tissue diseases, Child, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: Aged, Aged, 80 and over, Clinical Trials as Topic, MESH: Middle Aged, seroprevalence, MESH: Infant, Newborn, virus diseases, Middle Aged, MESH: Infant, [SDV] Life Sciences [q-bio], MESH: Young Adult, Child, Preschool, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Spike Glycoprotein, Coronavirus, Medicine, Female, France, Seasons, Research Paper, Adult, MESH: Pandemics, MESH: Clinical Trials as Topic, Adolescent, Cross Reactions, Young Adult, R5-920, MESH: Cross-Sectional Studies, Humans, MESH: SARS-CoV-2, Pandemics, Aged, MESH: Adolescent, MESH: Seroepidemiologic Studies, MESH: Humans, SARS-CoV-2, fungi, MESH: Child, Preschool, Infant, Newborn, COVID-19, Infant, MESH: Adult, antibody response, MESH: Male, respiratory tract diseases, Immunity, Humoral, MESH: France, Cross-Sectional Studies, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Seasons, MESH: Female, MESH: Antibodies, Viral
Abstract

Background: Children are underrepresented in the COVID-19 pandemic and often experience milder disease than adolescents and adults. Reduced severity is possibly due to recent and more frequent seasonal human coronaviruses (HCoV) infections. We assessed the seroprevalence of SARS-CoV-2 and seasonal HCoV specific antibodies in a large cohort in north-eastern France. Methods: In this cross-sectional seroprevalence study, serum samples were collected from children and adults requiring hospital admission for non-COVID-19 between February and August 2020. Antibody responses to SARS-CoV-2 and seasonal HCoV (229E, HKU1, NL63, OC43) were assessed using a bead-based multiplex assay, Luciferase-Linked ImmunoSorbent Assay, and a pseudotype neutralisation assay. Findings: In 2,408 individuals, seroprevalence of SARS-CoV-2-specific antibodies was 7-8% with three different immunoassays. Antibody levels to seasonal HCoV increased substantially up to the age of 10. Antibody responses in SARS-CoV-2 seropositive individuals were lowest in adults 18-30 years. In SARS-CoV-2 seronegative individuals, we observed cross-reactivity between antibodies to the four HCoV and SARS-CoV-2 Spike. In contrast to other antibodies to SARS-CoV-2, specific antibodies to sub-unit 2 of Spike (S2) in seronegative samples were highest in children. Upon infection with SARS-CoV-2, antibody levels to Spike of betacoronavirus OC43 increased across the whole age spectrum. No SARS-CoV-2 seropositive individuals with low levels of antibodies to seasonal HCoV were observed. Interpretation: Our findings underline significant cross-reactivity between antibodies to SARS-CoV-2 and seasonal HCoV, but provide no significant evidence for cross-protective immunity to SARS-CoV-2 infection due to a recent seasonal HCoV infection. In particular, across all age groups we did not observe SARS-CoV-2 infected individuals with low levels of antibodies to seasonal HCoV. Funding: This work was supported by the « URGENCE COVID-19 » fundraising campaign of Institut Pasteur, by the French Government's Investissement d'Avenir program, Laboratoire d'Excellence Integrative Biology of Emerging Infectious Diseases (Grant No. ANR-10-LABX-62-IBEID), and by the REACTing (Research & Action Emerging Infectious Diseases), and by the RECOVER project funded by the European Union's Horizon 2020 research and innovation programme under grant agreement No. 101003589, and by a grant from LabEx IBEID (ANR-10-LABX-62-IBEID).

Published
2021

2. Early assessment of diffusion and possible expansion of SARS-CoV-2 Lineage 20I/501Y.V1 (B.1.1.7, variant of concern 202012/01) in France, January to March 2021

Author

Gaymard, Alexandre, Bosetti, Paolo, Feri, Adeline, Destras, Gregory, Enouf, Vincent, Andronico, Alessio, Burrel, Sonia, Behillil, Sylvie, Sauvage, Claire, Bal, Antonin, Morfin, Florence, Van Der Werf, Sylvie, Josset, Laurence, Blanquart, François, Coignard, Bruno, Cauchemez, Simon, Lina, Bruno, Gault, Elyanne, Moreau, Frédérique, Brichler, Ségolène, Delagrèverie, Héloïse, Descamps, Diane, Charpentier, Charlotte, Rozenberg, Flore, L'Honneur, Anne-Sophie, Veyer, David, Bélec, Laurent, Fourati, Slim, Rodriguez, Christophe, Pawlotsky, Jean-Michel, Fourgeaud, Jacques, Abid, Hanène, Roque-Afonso, Anne-Marie, Fenaux, Honorine, Jary, Aude, Marot, Stéphane, Salmona, Maud, Chaix, Marie-Laure, Morand-Joubert, Laurence, Schnuriger, Aurélie, Juillet, Stéphanie Marque, Bargain, Pauline, Poggi, Cécile, Chollet, Lionel, Guillaume, Clémence, Guinard, Jérôme, Vallet, Sophie, Pilorgé, Léa, Schvoerer, Evelyne, Hartard, Cédric, Castelain, Sandrine, François, Catherine, Ducancelle, Alexandra, Lefeuvre, Caroline, Lepiller, Quentin, Marty-Quinternet, Solène, Bellecave, Pantxika, Tumiotto, Camille, Dina, Julia, Le Gouil, Meriadeg, Henquell, Cécile, Mirand, Audrey, Césaire, Raymond, de Rougemont, Alexis, Auvray, Christelle, Larrat, Sylvie, Némoz, Benjamin, Tinez, Claire, Guigon, Aurélie, Hantz, Sébastien, Rogez, Sylvie, Dos Santos, Georges, Perez, Pascale, Jost, Christelle, Montes, Brigitte, Foulongne, Vincent, Imbert, Berthe-Marie, Bressollette, Céline, Giordanengo, Valérie, Gonfrier, Géraldine, Garcia, Magali, Lévêque, Nicolas, Brodard, Véronique, Moret, Hélène, Thibault, Vincent, Maillard, Anne, Jaffar-Bandjee, Marie-Christine, Gueudin, Marie, Plantier, Jean-Christophe, Pozzetto, Bruno, Pillet, Sylvie, Fafi-Kremer, Samira, Solis, Morgane, Izopet, Jacques, Trémeaux, Pauline, Stefic, Karl, Handala, Lynda, Billaud, Geneviève, Frobert, Emilie, Mérens, Audrey, Bigaillon, Christine, Desroches, Marine, Thepenier, Cédric, Janvier, Frédéric, Otto, Marie-Pierre, Roquebert, Bénédicte, Haïm-Boukobza, Stéphanie, Centre National de Référence des Virus des Infections Respiratoires (dont la Grippe) [Lyon] (CNR - laboratoire associé), Institut des Agents Infectieux [Lyon] (IAI), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Hospices Civils de Lyon (HCL), Virpath-Grippe, de l'émergence au contrôle -- Virpath-Influenza, from emergence to control (Virpath), 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), Modélisation mathématique des maladies infectieuses - Mathematical modelling of Infectious Diseases, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Direction des maladies infectieuses - Infectious Diseases Division [Saint-Maurice], Santé publique France - French National Public Health Agency [Saint-Maurice, France], Centre National de Référence des virus des infections respiratoires (dont la grippe) - National Reference Center Virus Influenzae [Paris] (CNR - laboratoire coordonnateur), Institut Pasteur [Paris] (IP), Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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, Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Laboratoire de Virologie [CHU Amiens], CHU Amiens-Picardie, ANRS - Maladies infectieuses émergentes (ANRS - MIE), Institut National de la Santé et de la Recherche Médicale (INSERM), We acknowledge financial support from Santé publique France (the French national public health agency), the French Ministry of health (Grant COVIDseq), the Consortium for the surveillance and research on emerging pathogens via microbial genomics (EMERGEN) coordinated by Santé publique France and ANRS Maladies Infectieuses Emergentes, the Investissement d’Avenir programme, the Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases programme (grant ANR-10-LABX-62-IBEID), the European Union’s Horizon 2020 research and in-novation programme under grants 101003589 (RECOVER). This work has been supported by the laboratories belonging to the ColVHB network*., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), European Project: 101003589, H2020-SC1-PHE-CORONAVIRUS-2020,RECOVER(2020), Centre National de Référence des Virus des Infections Respiratoires (dont la Grippe) [Lyon] (CNR), 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), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre National de Référence des virus des infections respiratoires (dont la grippe) - National Reference Center Virus Influenzae [Paris] (CNR), Institut Pasteur [Paris], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Gestionnaire, Hal Sorbonne Université, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Rapid European COVID-19 Emergency Response research - RECOVER - - H2020-SC1-PHE-CORONAVIRUS-20202020-02-14 - 2022-02-13 - 101003589 - VALID, Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS 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)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris)

Subjects
Author's Correction, Paris, medicine.medical_specialty, 2019-20 coronavirus outbreak, Lineage (genetic), Coronavirus disease 2019 (COVID-19), Epidemiology, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), viral infections, [SDV]Life Sciences [q-bio], Context (language use), Biology, 03 medical and health sciences, 0302 clinical medicine, Virology, medicine, Humans, MESH: COVID-19, MESH: SARS-CoV-2, 030212 general & internal medicine, 030304 developmental biology, COVID, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 0303 health sciences, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, MESH: Humans, SARS-CoV-2, MESH: Paris, Public Health, Environmental and Occupational Health, COVID-19, [SDV] Life Sciences [q-bio], MESH: France, 20I/501Y.V1, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, surveillance, France, mutation, Rapid Communication, Demography
Abstract

International audience; The emergence of SARS-CoV-2 variant 20I/501Y.V1 (VOC-202012/1 or GR/501Y.V1) is concerning given its increased transmissibility. We reanalysed 11,916 PCR-positive tests (41% of all positive tests) performed on 7-8 January 2021 in France. The prevalence of 20I/501Y.V1 was 3.3% among positive tests nationwide and 6.9% in the Paris region. Analysing the recent rise in the prevalence of 20I/501Y.V1, we estimate that, in the French context, 20I/501Y.V1 is 52-69% more transmissible than the previously circulating lineages, depending on modelling assumptions.

Published
2021

3. The impact of pre-graft serology on the risk of BKPyV infection post-renal transplantation

Author

Fatima Dakroub, Toni Fiore, Gabriel Choukroun, Gilles Duverlie, Claire Tinez, Nicolas Guillaume, Claire Presne, Virginie Morel, François Helle, fadi Abdel Sater, Antoine Touzé, Catherine François, Haidar Akl, Etienne Brochot, Sandrine Castelain, Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Laboratory of Cancer Biology and Molecular Immunology [Beyrouth, Liban], Lebanese University [Beirut] (LU), Infectiologie et Santé Publique (UMR ISP), Université de Tours-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire de Virologie [CHU Amiens], CHU Amiens-Picardie, Unité de Transplantation Rénale et Pancréatique [CHU Sud, Amiens] (Service de Néphrologie), HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
Male, medicine.medical_treatment, 030232 urology & nephrology, BKPyV, kidney transplantation, Viremia, BKPyV virus serology, Serology, 03 medical and health sciences, 0302 clinical medicine, Medicine, Humans, serological technique, Kidney transplantation, Retrospective Studies, Transplantation, Polyomavirus Infections, BKPyV seroprevalence, business.industry, Incidence (epidemiology), Antibody titer, Immunosuppression, BKVPyV serostatus, medicine.disease, Transplant Recipients, 3. Good health, Tumor Virus Infections, Nephrology, BK Virus, Immunology, Female, business, Serostatus, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology
Abstract

Objectives BK polyomavirus-associated nephropathy is a troublesome disease caused by BK polyomavirus (BKPyV) infection in immunocompromised renal graft recipients. There are no effective treatments available, making immunosuppression reduction the only management option. Thus, pre-graft predictive BKPyV replication markers are needed for identification of patients at high risk of viraemia. Methods We conducted a retrospective study to assess the correlation between pre-transplantation BKPyV serostatus and post-transplantation incidence of BKPyV infection. Sera from 329 recipients and 222 matched donors were tested for anti-BKPyV antibodies against BKPyV serotypes I and IV by using a virus-like particle-based immunoglobulin G enzyme-linked immunosorbent assay, and BKPyV DNA load was monitored for at least 1 year post-transplantation. Results Eighty recipients were viruric and 59 recipients were viraemic post-transplantation. In the post-transplantation period, the probability of developing viraemia for serotype I increased from 4.3% for the D−/R+ group to 12.1% for the D+/R+ group, climbing to 37.5% for the D+/R− group (P Conclusions Determination of both donor and recipient BKPyV seropositivity before transplantation and antibody titre measurements may serve as a predictive tool to manage clinical BKPyV infection by identification of patients at high risk.

Published
2021

4. A simple score (Biovid-19) based on biological parameters predicts transfer to intensive care units and death in COVID-19 patients

Author

Guillaume Couillez, Julien Maizel, Thomas Boyer, Jean-Luc Schmit, Ophélie Evrard, Etienne Brochot, Alexis Caulier, Catherine François, Rémy Nyga, Chloé Sauzay, Claire Andrejak, Sandrine Castelain, Loïc Garçon, Maïlys Le Guyader, DESSAIVRE, Louise, WEB Architecture x Semantic WEB x WEB of Data (WEB3), Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier (LIRMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), CHirurgie, IMagerie et REgénération tissulaire de l’extrémité céphalique - Caractérisation morphologique et fonctionnelle - UR UPJV 7516 (CHIMERE), Université de Picardie Jules Verne (UPJV), CHU Amiens-Picardie, Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Eugène Marquis (CRLCC), Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Parasitologie-Mycologie [CHRU LIlle], Institut de Microbiologie [CHRU Lille], Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de Virologie [CHU Amiens], Mécanismes physiopathologiques et conséquences des calcifications vasculaires - UR UPJV 7517 (MP3CV), and Laboratoire d'Hématologie [CHU Amiens]

Subjects
Adult, Male, Patient Transfer, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), [SDV]Life Sciences [q-bio], Risk Assessment, Severity of Illness Index, General Biochemistry, Genetics and Molecular Biology, Cohort Studies, Young Adult, Intensive care, Transfer (computing), Severity of illness, medicine, Humans, Hospital Mortality, Patient transfer, Letter to the Editor, ComputingMilieux_MISCELLANEOUS, Aged, Retrospective Studies, Aged, 80 and over, business.industry, SARS-CoV-2, Sodium, COVID-19, Retrospective cohort study, General Medicine, Middle Aged, Prognosis, Triage, Death, [SDV] Life Sciences [q-bio], Intensive Care Units, Research Design, Emergency medicine, Potassium, Female, France, business, Biomarkers, Blood Chemical Analysis, Cohort study
Abstract

International audience; No abstract available

Published
2021

5. Invasive Tracheobronchial Aspergillosis in Critically Ill Patients with Severe Influenza. A Clinical Trial

Author

Saad Nseir, Anne Totet, Malcolm Lemyze, Michel Slama, Elie Zogheib, Ivona Milic, Rémy Nyga, Hervé Dupont, Pierre-Alexandre Roger, Sandrine Castelain, Julien Maizel, Nicolas Van Grunderbeeck, Boualem Sendid, Taieb Chouaki, CHU Amiens-Picardie, Mécanismes physiopathologiques et conséquences des calcifications vasculaires - UR UPJV 7517 (MP3CV), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de parasitologie et de mycologie médicales [CHU Amiens], Centre Hospitalier de Lens, Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Laboratoire de Virologie [CHU Amiens], Simplification des soins chez les patients complexes - UR UPJV 7518 (SSPC), Université de Picardie Jules Verne (UPJV), Service de Parasitologie-Mycologie [CHRU LIlle], Institut de Microbiologie [CHRU Lille], Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Lille Inflammation Research International Center - U 995 (LIRIC), 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 Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, [SDV]Life Sciences [q-bio], macromolecular substances, Critical Care and Intensive Care Medicine, Aspergillosis, Severe influenza, 03 medical and health sciences, Galactomannan, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, aspergillosis, 030212 general & internal medicine, (1-3)-β-d-glucan, business.industry, Critically ill, Invasive pulmonary aspergillosis, medicine.disease, 3. Good health, Clinical trial, 030228 respiratory system, chemistry, galactomannan, ICU, business, influenza, 1 3 β d glucan
Abstract

International audience; Rationale: Invasive tracheobronchial aspergillosis (ITBA) is an uncommon but severe clinical form of invasive pulmonary aspergillosis in which the fungal infection is entirely or predominantly confined to the tracheobronchial tree.Objectives: To analyze the diagnostic and prognostic differences between tracheobronchial aspergillosis and pulmonary aspergillosis without tracheobronchial lesions among patients admitted to the ICU with severe influenza.Methods: This retrospective, observational study included critically ill patients with influenza associated with pulmonary aspergillosis from three hospital ICUs between 2010 and 2019. Patient characteristics and clinical and mycologic data at admission and during ICU stay were collected in a database to evaluate variables in the two groups.Measurements and Main Results: Thirty-five patients admitted to the ICU with severe influenza and pulmonary aspergillosis were included. Ten patients were included in the group with ITBA (n = 10 of 35; 28.6%), and 25 patients were included in the group without ITBA. The group with ITBA comprised more patients with active smoking, diabetes mellitus, and higher severity scores (Simplified Acute Physiology Score II). Ninety-day mortality rates in the groups with and without ITBA were 90% and 44%, respectively (P = 0.02). Moreover, significantly higher serum 1,3-β-d-glucan and galactomannan and BAL fluid galactomannan concentrations were observed in the group with ITBA compared with the group without ITBA (P

Published
2020

6. BK Polyomavirus Hijacks Extracellular Vesicles for En Bloc Transmission

Author

Gilles Duverlie, Etienne Brochot, François Helle, Lynda Handala, Pierre-Ivan Raynal, Sandrine Castelain, Philippe Roingeard, Catherine François, Emmanuelle Blanchard, Virginie Morel, Véronique Descamps, Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Laboratoire de Virologie [CHU Amiens], CHU Amiens-Picardie, 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), Plateforme IBISA de Microscopie Electronique [CHRU de Tours] (UNIV Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT), and DESSAIVRE, Louise

Subjects
en bloc transmission, MCPyV, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Immunology, Cell, quasienveloped virus, polyomavirus, BKPyV, Biology, Endocytosis, Microbiology, Virus, Pathogenesis, 03 medical and health sciences, SV40, Extracellular Vesicles, Immune system, Virology, Chlorocebus aethiops, medicine, Animals, neutralizing antibodies, Spotlight, Vero Cells, 030304 developmental biology, 0303 health sciences, Polyomavirus Infections, 030306 microbiology, Immunosuppression, JCPyV, medicine.disease, Transplant rejection, Virus-Cell Interactions, [SDV] Life Sciences [q-bio], TSPyV, medicine.anatomical_structure, Insect Science, BK Virus, biology.protein, Antibody
Abstract

Reactivation of BKPyV is responsible for nephropathies in kidney transplant recipients, which frequently lead to graft loss. The mechanisms of persistence and immune evasion used by this virus remain poorly understood, and a therapeutic option for transplant patients is still lacking. Here, we show that BKPyV can be released into EVs, enabling viral particles to infect cells using an alternative entry pathway. This provides a new view of BKPyV pathogenesis. Even though we did not find any decreased sensitivity to neutralizing antibodies when comparing EV-associated particles and naked virions, our study also raises important questions about developing prevention strategies based on the induction or administration of neutralizing antibodies. Deciphering this new release pathway could enable the identification of therapeutic targets to prevent BKPyV nephropathies. It could also lead to a better understanding of the pathophysiology of other polyomaviruses that are associated with human diseases., Most people are asymptomatic carriers of the BK polyomavirus (BKPyV), but the mechanisms of persistence and immune evasion remain poorly understood. Furthermore, BKPyV is responsible for nephropathies in kidney transplant recipients. Unfortunately, the sole therapeutic option is to modulate immunosuppression, which increases the risk of transplant rejection. Using iodixanol density gradients, we observed that Vero and renal proximal tubular epithelial infected cells release two populations of infectious particles, one of which cosediments with extracellular vesicles (EVs). Electron microscopy confirmed that a single vesicle could traffic tens of viral particles. In contrast to naked virions, the EV-associated particles (eBKPyVs) were not able to agglutinate red blood cells and did not use cell surface sialylated glycans as an attachment factor, demonstrating that different entry pathways were involved for each type of infectious particle. However, we also observed that naked BKPyV and eBKPyV were equally sensitive to neutralization by the serum of a seropositive patient or commercially available polyvalent immunoglobulin preparations, which occurred at a postattachment step, after endocytosis. In conclusion, our work shows a new mechanism that likely plays a critical role during the primary infection and in the persistence, but also the reactivation, of BKPyV. IMPORTANCE Reactivation of BKPyV is responsible for nephropathies in kidney transplant recipients, which frequently lead to graft loss. The mechanisms of persistence and immune evasion used by this virus remain poorly understood, and a therapeutic option for transplant patients is still lacking. Here, we show that BKPyV can be released into EVs, enabling viral particles to infect cells using an alternative entry pathway. This provides a new view of BKPyV pathogenesis. Even though we did not find any decreased sensitivity to neutralizing antibodies when comparing EV-associated particles and naked virions, our study also raises important questions about developing prevention strategies based on the induction or administration of neutralizing antibodies. Deciphering this new release pathway could enable the identification of therapeutic targets to prevent BKPyV nephropathies. It could also lead to a better understanding of the pathophysiology of other polyomaviruses that are associated with human diseases.

Published
2020

7. Anti-spike, Anti-nucleocapsid and Neutralizing Antibodies in SARS-CoV-2 Inpatients and Asymptomatic Individuals

Author

Etienne Brochot, Baptiste Demey, Antoine Touzé, Sandrine Belouzard, Jean Dubuisson, Jean-Luc Schmit, Gilles Duverlie, Catherine Francois, Sandrine Castelain, Francois Helle, Laboratoire de Virologie [CHU Amiens], CHU Amiens-Picardie, Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Infectiologie et Santé Publique (UMR ISP), Université de Tours-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), 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), Flash Covid-19 funds from the Amiens University Hospital and the French 'Agence Nationale de la Recherche', Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), 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), ANR-21-COVR-0022,ANTICOV,Valeur pronostique des auto-anticorps ANTi-Interféron de type I chez les patients pris en charge pour un syndrome de détresse respiratoire aiguë associé au COVID-19 : une étude de cohorte observationnelle multicentriq(2021), and Belouzard, Sandrine

Subjects
Microbiology (medical), Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), convalescent plasma therapy, lcsh:QR1-502, nucleocapsid, Asymptomatic, Microbiology, lcsh:Microbiology, Serology, 03 medical and health sciences, Immune system, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, vaccine, Medicine, neutralizing antibodies, Seroconversion, Neutralizing antibody, 030304 developmental biology, Original Research, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 0303 health sciences, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, biology, 030306 microbiology, business.industry, SARS-CoV-2, COVID-19, spike, Virology, 3. Good health, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, biology.protein, Antibody, medicine.symptom, business
Abstract

International audience; A better understanding of the anti-SARS-CoV-2 immune response is necessary to finely evaluate commercial serological assays but also to predict protection against reinfection and to help the development of vaccines. For this reason, we monitored the anti-SARS-CoV-2 antibody response in infected patients. In order to assess the time of seroconversion, we used 151 samples from 30 COVID-19 inpatients and monitored the detection kinetics of anti-S1, anti-S2, anti-RBD and anti-N antibodies with in-house ELISAs. We observed that specific antibodies were detectable in all inpatients 2 weeks post-symptom onset and that the detection of the SARS-CoV-2 Nucleocapsid and RBD was more sensitive than the detection of the S1 or S2 subunits. Using retroviral particles pseudotyped with the spike of the SARS-CoV-2, we also monitored the presence of neutralizing antibodies in these samples as well as 25 samples from asymptomatic individuals that were shown SARS-CoV-2 seropositive using commercial serological tests. Neutralizing antibodies reached a plateau 2 weeks post-symptom onset and then declined in the majority of inpatients but they were undetectable in 56% of asymptomatic patients. Our results indicate that the SARS-CoV-2 does not induce a prolonged neutralizing antibody response. They also suggest that induction of neutralizing antibodies is not the only strategy to adopt for the development of a vaccine. Finally, they imply that anti-SARS-CoV-2 neutralizing antibodies should be titrated to optimize convalescent plasma therapy.

Published
2020

8. MICA and NKG2D variants as risk factors in spondyloarthritis: a case–control study

Author

Judith Desoutter, Etienne Brochot, Gauthier Delvallez, Vincent Goëb, Nicolas Guillaume, Marie Fechtenbaum, Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Amiens-Picardie, Centre hospitalier territorial Gaston-Bourret [Nouméa], Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Laboratoire de Virologie [CHU Amiens], CEA-LETI - Commissariat à l'énergie atomique et aux énergies alternatives - Laboratoire d'Electronique et de Technologie de l'Information, Service de rhumatologie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), and CRI-IMIDIATE Clinical Research Network

Subjects
Male, 0301 basic medicine, [SDV]Life Sciences [q-bio], Genes, MHC Class I, CD8-Positive T-Lymphocytes, chemistry.chemical_compound, 0302 clinical medicine, Gene Frequency, Risk Factors, Odds Ratio, Cytotoxic T cell, Child, Genetics (clinical), Middle Aged, Killer Cells, Natural, NK Cell Lectin-Like Receptor Subfamily K, Female, Adult, medicine.medical_specialty, Adolescent, Immunology, Biology, Major histocompatibility complex, White People, Article, 03 medical and health sciences, Psoriatic arthritis, Internal medicine, Spondylarthritis, Genetics, medicine, Humans, Genetic Predisposition to Disease, Reactive arthritis, Allele, Alleles, Aged, Retrospective Studies, Genetic association study, Polymorphism, Genetic, Methionine, Histocompatibility Antigens Class I, Genetic Variation, medicine.disease, NKG2D, stomatognathic diseases, 030104 developmental biology, Endocrinology, chemistry, Case-Control Studies, biology.protein, CD8, 030215 immunology
Abstract

International audience; The major histocompatibility complex class I polypeptide-related sequence A (MICA) glycoprotein mediates the activation of the natural killer group 2D receptor (NKG2D) expressed on NK and CD8+ T cells. A methionine or valine at position 129 in exon 3 results in strong (MICA129 met) or weak (MICA129 val) binding to NKG2D. The MICA A5.1 allele causes a premature stop codon. Various NKG2D polymorphisms are associated with low (NKC3 C/C and NKC4 C/C) or high (NKC3 G/G and NKC4 T/T) levels of NK cell cytotoxic activity. In 162 patients with spondyloarthritis (115 with ankylosing spondyloarthritis, 46 with psoriatic arthritis and 1 with reactive arthritis) compared to 124 healthy controls, MICA-129 with methionine allele was more frequent in patients with spondyloarthritis (odds ratio (OR) (95% confidence interval) = 4.84 (2.75-8.67)), whereas MICA-129 val/val, MICA A5.1 and NKC3 C/C variants were less frequent (OR = 0.20 (0.11-0.37), 0.15 (0.06-0.36) and 0.24 (0.13-0.44), respectively). After adjustment for HLA-B*27 status, only NKC3 C/C remained linked to spondyloarthritis (adjusted OR = 0.14 (0.06-0.33)). Homozygosity for MICA A5.1 is linked to ankylosing spondyloarthritis, and NKC3 C/C and MICA-129 val/val to psoriatic arthritis. MICA and NKC3 polymorphisms (related to a low NK cell cytotoxic activity) constituted a genetic association with spondyloarthritis.

Published
2018

9. COVID-19 encephalopathy: detection of antibodies against SARS-CoV-2 in CSF

Author

William Thibault, Sandrine Castelain, Daniela Andriuta, Bénédicte Toublanc, Chloé Sauzay, Pierre Alexandre Roger, Etienne Brochot, Olivier Godefroy, Service de neurologie [Amiens], CHU Amiens-Picardie, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), Mécanismes physiopathologiques et conséquences des calcifications vasculaires - UR UPJV 7517 (MP3CV), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Centre Eugène Marquis (CRLCC), Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Laboratoire de Virologie [CHU Amiens], Institut du Cerveau = Paris Brain Institute (ICM), 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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and DESSAIVRE, Louise

Subjects
2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), biology, business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), [SDV]Life Sciences [q-bio], Encephalopathy, Clinical Neurology, medicine.disease, Virology, Letter to the Editors, [SDV] Life Sciences [q-bio], Neurology, Pandemic, biology.protein, Medicine, Neurology (clinical), Antibody, business, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2020

10. Fast CMV and EBV Reactivations after Ruxolitinib for Graft-Versus-Host Disease Treatment

Author

Delphine Lebon, Marie-Noëlle Lacassagne, Berengere Gruson, Sandrine Castelain, Magalie Joris, Dujardin Adèle, Pierre Morel, Jean-Pierre Marolleau, Marine Quint, Amandine Charbonnier, Alexis Caulier, Laboratoire de Physique des Plasmas (LPP), Université Paris-Sud - Paris 11 (UP11)-Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École polytechnique (X)-Sorbonne Université (SU)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), CHU Amiens-Picardie, HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Picardie Jules Verne (UPJV), Laboratoire Chrono-environnement (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), Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Laboratoire de Virologie [CHU Amiens], Service clinique des Maladies du Sang, and DESSAIVRE, Louise

Subjects
First episode, medicine.medical_specialty, Cyclophosphamide, business.industry, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Immunology, Cell Biology, Hematology, Hematopoietic stem cell transplantation, medicine.disease, Biochemistry, Gastroenterology, [SDV] Life Sciences [q-bio], Graft-versus-host disease, Internal medicine, Acute lymphocytic leukemia, medicine, Cumulative incidence, business, Viral load, Myeloproliferative neoplasm, medicine.drug
Abstract

Introduction: Corticosteroid-refractory graft-versus-host disease (GVHD) remains a serious complication of hematopoietic stem cell transplantation (HSCT) with high morbidity and mortality rates. Unfortunately, no standard therapy exists for this setting. Ruxolitinib (ruxo), an oral selective Janus-associated kinase (JAK) inhibitor, achieved good results for corticoresistant acute and chronic GVHD in preclinical and clinical studies, with 80% overall response rates. Recent studies showed an increased risk of infections in patients treated with ruxo, especially Epstein-Barr virus (EBV) and cytomegalovirus (CMV) reactivations. Patients and methods: In order to assess the efficacy and the safety of ruxo, we reviewed here the outcome of 57 patients who received ruxo for corticosteroid-refractory GVHD (in case of digestive tract involvement or in the absence of available ongoing clinical trials) or as a steroids-sparing medication. EBV and CMV reactivation risks were also assessed in the 137 consecutive patients received HSCT between January 1, 2012 and December 31, 2017 and who presented acute or chonic GVHD (57 of whom received ruxo). For this purpose, each reactivation were analyzed separately as a competing risk with death in a cause specific Cox model of survival after the first GVHD occurrence and the onset of ruxo therapy was coded as time dependent covariate. Results: The median age of 57 patients with ruxo was 55 years (range, 49 to 61). Indication for HSCT was acute myeloid leukemia for 25% patients, lymphoma for 30%, acute lymphoblastic leukemia for 11%, myeloproliferative neoplasm for 14% and myelodysplastic syndrome for 7%. Only 9% of this patients received ruxo before HSCT. Unrelated donor was used for 60% patients and main source of hematopoietic stem cells was peripheral stem cells (93%). T cell depletion with polyclonal anti-thymocyte globulin was performed for 89% of patients. Conditioning with high doses cyclophosphamide was used for 21% patients. A lymphopenia 4 log or increasing viral charge of 0.5 log) occurred in 19 patients after ruxo with a 6-weeks cumulative incidence (6WCuI) of 22% (95CI [95% confidence interval]: 15-34). It was the first reactivation in 13 patients. CMV reactivation (> 3 log) occurred in 8 patients after ruxo with a 6WCuI of 4% (95CI: 7-25). It was the first reactivation in 3 patients (Figure 1). The distribution of first reactivation before ruxo and in the remaining 80 patients is shown in Table 1. Thus, 6WCuI of first EBV and CMV reactivation after the first episode of GVHD was 24% (95CI: 19-31) and 20% (95CI: 15-25) respectively. Finally, onset of ruxo coded as time dependent covariates retained a significant adverse prognostic value for the competing risks of death and first episode of EBV reactivation (HR [Hazard Ratio]: 2,657, p Discussion /Conclusion: Ruxo initiation coded as a time-dependent covariate was significantly associated with the overall risk of viral reactivation after the first episode of GVHD and the viral reactivations incidences after ruxo were similar with the incidence of reactivation at the onset of GVHD. Thus, it might be linked to the immuno-compromised state induced by both HSCT and GVHD. Furthermore, as we used ruxo for serious gastro intestinal GVHD, we could have selected patients with a more severe GVHD, requiring multiple immunosuppressive therapy, worsening immune reconstitution. To our knowledge it is the first study to assess the competing risk of CMV and EBV reactivation during ruxo treatment for GVHD. Given its effectiveness in corticoresistant GVHD, ruxo use must not be limited by the fear of viral reactivation at the light of our data, conditioned upon a close monitoring of viral loads in the first weeks. Disclosures No relevant conflicts of interest to declare.

Published
2019

11. Identification of Conserved Residues in Hepatitis C Virus Envelope Glycoprotein E2 That Modulate Virus Dependence on CD81 and SRB1 Entry Factors

Author

Muriel Lavie, Thomas F. Baumert, Karin Séron, François Penin, Véronique Descamps, Jean Dubuisson, Roland Montserret, Stéphane Sarrazin, Gilles Duverlie, Département d'Architectures, Conception et Logiciels Embarqués-LIST (DACLE-LIST), Laboratoire d'Intégration des Systèmes et des Technologies (LIST), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, 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), Service de dermatologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), Universität Kassel [Kassel], Génétique des maladies multifactorielles (GMM), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Naiglin, Laurence, 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)), Laboratoire de Virologie [CHU Amiens], CHU Amiens-Picardie, Plate-forme de R&D - Puces à Cellules Transfectées (PCT), Cancéropôle du Grand-Est (CGE)-Centre Européen de Biologie et de Génomique Structurale (CEBGS), Unité de Virologie clinique et fondamentale (UVCF), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and 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)

Subjects
Models, Molecular, Virus genetics, [SDV]Life Sciences [q-bio], Immunology, Sequence alignment, Plasma protein binding, Hepacivirus, Biology, Microbiology, Virus, Conserved sequence, Tetraspanin 28, Viral Envelope Proteins, Virology, Humans, Amino Acid Sequence, Peptide sequence, Conserved Sequence, ComputingMilieux_MISCELLANEOUS, Genetics, Lipid bilayer fusion, Scavenger Receptors, Class B, Virus Internalization, Hepatitis C, 3. Good health, Virus-Cell Interactions, [SDV] Life Sciences [q-bio], Viral Receptor, Insect Science, Receptors, Virus, Sequence Alignment, Protein Binding
Abstract

In spite of the high variability of its sequence, hepatitis C virus (HCV) envelope glycoprotein E2 contains several conserved regions. In this study, we explored the structural and functional features of the highly conserved E2 segment from amino acid (aa) 502 to 520, which had been proposed as a fusion peptide and shown to strongly overlap a potential conserved neutralizing epitope. For this purpose, we used reverse genetics to introduce point mutations within this region, and we characterized the phenotypes of these mutants in the light of the recently published structure of E2. The functional analyses showed that their phenotypes are in agreement with the positions of the corresponding residues in the E2 crystal structure. In contrast, our data ruled out the involvement of this region in membrane fusion, and they indicate that alternative conformations would be necessary to expose the potential neutralizing epitope present in this segment. Of particular interest, we identified three specific mutations (Y507L, V514A, and V515A) located within this neutralizing epitope which only mildly reduced infectivity and showed no assembly defect. These mutations modulated HCV dependence on the viral receptor SRB1, and/or they also modulated virion sensitivity to neutralizing antibodies. Importantly, their characterization also showed that amino acids Y507, V514, and V515 contribute to E2 interaction with HCV receptor CD81. In conclusion, our data show that the highly conserved E2 segment from aa 502 to 520 plays a key role in cell entry by influencing the association of the viral particle with coreceptors and neutralizing antibodies. IMPORTANCE Hepatitis C virus (HCV) envelope proteins E1 and E2 exhibit sequence variability. However, some segments of the envelope proteins are highly conserved, suggesting that these sequences play a key role at some steps of the HCV life cycle. In this work, we characterized the function and structure of a highly conserved E2 region that is targeted by neutralizing antibodies and had been proposed as a fusion peptide. Our data ruled out the involvement of this region in membrane fusion but allowed for the identification of new residues modulating the interaction of the virus with entry factors and its sensitivity to neutralizing antibodies. Moreover, structural data suggest that alternative conformations could exist for E2, which would explain the presence of a partially masked neutralizing epitope in this segment in the currently available E2 structure. Overall, our findings highlight the importance of conserved regions in the sequences of HCV envelope proteins.

Published
2014

12. Multicenter quality control of hepatitis C virus protease inhibitor resistance genotyping

Author

Evelyne Schvoerer, Elisabeth André-Garnier, Joël Gozlan, Etienne Brochot, Sylvie Larrat, Sébastien Hantz, Catherine Gaudy-Graffin, Hélène Le Guillou-Guillemette, Nelly Magnat, Vincent Mackiewicz, Syria Laperche, Jean-Christophe Plantier, Philippe Colson, Françoise Lunel-Fabiani, Patrick Soussan, Gisèle Lagathu, Christopher Payan, Jacques Izopet, Sylvain Rosec, S. Gouriou, Anne-Marie Roque-Afonso, Patrice Morand, Caroline Scholtes, Adeline Pivert, Sophie Vallet, Florence Legrand-Abravanel, Vincent Thibault, Sarah Maylin, Audrey Mirand, Stéphane Chevaliez, Jean-Michel Pawlotsky, Charlotte Charpentier, Valérie Giordanengo, Cécile Henquell, Françoise Bouchardeau, Lina Aguilera, Pascale Trimoulet, Laboratoire Universitaire de Biodiversité et Ecologie Microbienne (LUBEM), Université de Brest (UBO), Laboratoire de virologie moléculaire et structurale (LVMS), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Centre National de Référence Virus des hépatites B, C et Delta, Institut National de la Transfusion Sanguine [Paris] (INTS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de virologie, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Virologie [Rennes] = Virology [Rennes], CHU Pontchaillou [Rennes], 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, CHU Strasbourg, Virus, pseudo-virus: Morphogénèse et Antigénicité, Université de Tours-EA3856, CHU Bordeaux [Bordeaux], Laboratoire de Virologie [CHU Amiens], CHU Amiens-Picardie, Unité de Virologie clinique et fondamentale (UVCF), CHU Amiens-Picardie-Université de Picardie Jules Verne (UPJV), Service de Bactériologie, Virologie, Hygiène [CHU Limoges], CHU Limoges, 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse, Carcinogenèse Hépatique et Virologie Moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de virologie [Rouen], Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Département de microbiologie : Bactério, Virologie, Parasito, Hygiène-Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU), 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), 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), 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), Centre d'Investigation Clinique (CIC - Brest), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Virologie [Purpan], CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Université de Tours (UT)-EA3856, Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Département de microbiologie : Bactério, Virologie, Parasito, Hygiène, 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 Joseph Fourier - Grenoble 1 (UJF), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Service de virologie, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Service des maladies infectieuses et tropicales [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-Sorbonne Université, Université Nice Sophia Antipolis (1965 - 2019) (UNS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Institut des sciences biologiques (INSB-CNRS)-Institut des sciences biologiques (INSB-CNRS)-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], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)

Subjects
Microbiology (medical), Quality Control, MESH: Antiviral Agents, MESH: Sequence Analysis, DNA, MESH: Mutation, Genotype, Hepatitis C virus, Hepacivirus, [SDV]Life Sciences [q-bio], MESH: Quality Control, MESH: Amino Acid Sequence, Viral Nonstructural Proteins, MESH: Base Sequence, medicine.disease_cause, Antiviral Agents, MESH: Genotype, 03 medical and health sciences, 0302 clinical medicine, Virology, Drug Resistance, Viral, medicine, Protease inhibitor (pharmacology), Protease Inhibitors, MESH: Hepacivirus, Amino Acid Sequence, Genotyping, 0303 health sciences, NS3, MESH: Drug Resistance, Viral, MESH: Protease Inhibitors, biology, Base Sequence, 030306 microbiology, Inhibitor resistance, virus diseases, Sequence Analysis, DNA, biology.organism_classification, 3. Good health, Hcv protease, Mutation, MESH: Viral Nonstructural Proteins, 030211 gastroenterology & hepatology
Abstract

Hepatitis C virus (HCV) protease inhibitor resistance-associated substitutions are selected during triple-therapy breakthrough. This multicenter quality control study evaluated the expertise of 23 French laboratories in HCV protease inhibitor resistance genotyping. A panel of 12 well-defined blinded samples comprising two wild-type HCV strains, nine transcripts from synthetic NS3 mutant samples or from clinical strains, and one HCV RNA-negative sample was provided to the participating laboratories. The results showed that any laboratory with expertise in sequencing techniques should be able to provide reliable HCV protease inhibitor resistance genotyping. Only a 0.7% error rate was reported for the amino acid sites studied. The accuracy of substitution identification ranged from 75% to 100%, depending on the laboratory. Incorrect results were mainly related to the methodology used. The results could be improved by changing the primers and modifying the process in order to avoid cross-contamination. This study underlines the value of quality control programs for viral resistance genotyping, which is required prior to launching observational collaborative multicenter studies on HCV resistance to direct-acting antiviral agents.

Published
2013

13. Disulfide bonds in hepatitis C virus glycoprotein E1 control the assembly and entry functions of E2 glycoprotein

Author

Ahmed Wahid, François Helle, Gilles Duverlie, Jean Dubuisson, François Penin, Véronique Descamps, 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), Laboratoire de Virologie [CHU Amiens], CHU Amiens-Picardie, Unité de Virologie clinique et fondamentale (UVCF), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, 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), 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), 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, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)

Subjects
MESH: Virus Assembly, viruses, MESH: Virus Internalization, [SDV]Life Sciences [q-bio], Immunology, Hepacivirus, Microbiology, Virus, Cell Line, 03 medical and health sciences, MESH: Mutant Proteins, Viral Envelope Proteins, Virology, Humans, MESH: Disulfides, MESH: Hepacivirus, Cysteine, Disulfides, MESH: Reverse Genetics, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, MESH: Humans, biology, 030306 microbiology, Structure and Assembly, Virus Assembly, Virus Internalization, MESH: Cysteine, Herpesvirus glycoprotein B, Fusion protein, MESH: Amino Acid Substitution, Transmembrane protein, Reverse Genetics, 3. Good health, MESH: Cell Line, NS2-3 protease, MESH: Mutagenesis, Site-Directed, chemistry, Amino Acid Substitution, Insect Science, Chaperone (protein), MESH: Viral Envelope Proteins, biology.protein, Mutagenesis, Site-Directed, Mutant Proteins, Glycoprotein, CD81
Abstract

Class II membrane fusion proteins have been described in viruses in which the envelope proteins are derived from a precursor polyprotein containing two transmembrane glycoproteins arranged in tandem. Although the second protein, which carries the membrane fusion function, is in general well characterized, the companion protein, which is a protein chaperone for the folding of the fusion protein, is less well characterized for some viruses, like hepatitis C virus (HCV). To investigate the role of the class II companion glycoprotein E1 of HCV, we chose to target conserved cysteine residues in the protein, and we systematically mutated them in a full-length infectious HCV clone by reverse genetics. All the mutants were infectious, albeit with lower titers than the wild-type virus. The reduced infectivity was in part due to a decrease in viral assembly, as revealed by measurement of intracellular infectivity and by quantification of core protein released from cells transfected with mutant genomes. Analyses of mutated proteins did not show any major defect in folding. However, the mutations reduced virus stability, and they could also affect the density of infectious viral particles. Mutant viruses also showed a defect in cell-to-cell transmission. Finally, our data indicate that HCV glycoprotein E1 can also affect the fusion protein E2 by modulating its recognition by the cellular coreceptor CD81. Therefore, in the context of HCV, our data identify an additional function of a class II companion protein as a molecule that can control the binding capacity of the fusion protein.

Published
2013

14. The treatment response of chronically hepatitis C virus-infected patients depends on interferon concentration but not on interferon gene expression in peripheral blood mononuclear cells

Author

Gilles Duverlie, Cédric Coulouarn, Etienne Brochot, Véronique Descamps, Isabelle Duchaussoy, Sandrine Castelain, Dominique Capron, Agnès Baron, Catherine François, Eric Nguyen-Khac, Laboratoire de Virologie [CHU Amiens], CHU Amiens-Picardie, Unité de Virologie clinique et fondamentale (UVCF), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Foie, métabolismes et cancer, 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 ), Service d'Hépatogastroentérologie, Université de Rennes 1 (UR1), and 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 )

Subjects
Male, Hepacivirus, medicine.disease_cause, Polyethylene Glycols, MESH: Recombinant Proteins, chemistry.chemical_compound, 0302 clinical medicine, Interferon, Gene expression, Pharmacology (medical), MESH: Hepacivirus, MESH: Treatment Outcome, 0303 health sciences, MESH: Middle Aged, biology, Middle Aged, Viral Load, MESH: Gene Expression Regulation, Recombinant Proteins, 3. Good health, MESH: Hepatitis C, Chronic, MESH: Leukocytes, Mononuclear, Treatment Outcome, Infectious Diseases, Drug Therapy, Combination, Female, 030211 gastroenterology & hepatology, MESH: Interferon-alpha, MESH: Viral Load, Viral load, medicine.drug, Adult, MESH: Antiviral Agents, Hepatitis C virus, Alpha interferon, Interferon alpha-2, Antiviral Agents, Peripheral blood mononuclear cell, 03 medical and health sciences, MESH: Ribavirin, Ribavirin, medicine, Humans, 030304 developmental biology, Pharmacology, MESH: Humans, business.industry, Body Weight, Interferon-alpha, MESH: Adult, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Hepatitis C, Chronic, biology.organism_classification, MESH: Male, MESH: Body Weight, MESH: Drug Therapy, Combination, Gene Expression Regulation, chemistry, MESH: Polyethylene Glycols, Immunology, Leukocytes, Mononuclear, business, MESH: Female
Abstract

The current treatment of chronic hepatitis C is based on pegylated alpha interferon (PEG-IFN-α) and ribavirin. The aim of this study was to identify biological and clinical variables related to IFN therapy that could predict patient outcome. The study enrolled 47 patients treated with PEG-IFN and ribavirin combined therapy. The interferon concentration was measured in serum by a bioassay. The expression of 93 interferon-regulated genes in peripheral blood mononuclear cells was quantified by real-time quantitative reverse transcription-PCR (RT-PCR) before and after 1 month of treatment. The interferon concentration in the serum was significantly lower in nonresponders than in sustained virological responders. Moreover, a significant correlation was identified between interferon concentration and interferon exposition as well as body weight. The analysis of interferon-inducible genes in peripheral blood mononuclear cells among the genes tested did not permit the prediction of treatment outcome. In conclusion, the better option seems to be to treat patients with weight-adjusted PEG-IFN doses, particularly for patients with high weight who are treated with PEG-IFN-α2a. Although the peripheral blood mononuclear cell samples are the easiest to obtain, the measurement of interferon-inducible genes seems not be the best strategy to predict treatment outcome.

Published
2012

15. Relationship between the hepatitis C viral load and the serum interferon concentration during the first week of peginterferon-alpha-2b-ribavirin combination therapy

Author

Sandrine Castelain, Etienne Brochot, Isabelle Bernard, Véronique Descamps, Valérie Canva, Catherine François, Gilles Duverlie, Philippe Mathurin, Laboratoire de Virologie [CHU Amiens], CHU Amiens-Picardie, Unité de Virologie clinique et fondamentale (UVCF), CHU Amiens-Picardie-Université de Picardie Jules Verne (UPJV), Service d'Hépato-gastroentérologie, Hôpital Huriez-Université de Lille, and Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie

Subjects
Male, Serum, Combination therapy, Genotype, Hepatitis C virus, Hepacivirus, Alpha interferon, Interferon alpha-2, medicine.disease_cause, Antiviral Agents, Polyethylene Glycols, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Blood serum, Virology, Ribavirin, medicine, Humans, 030304 developmental biology, 0303 health sciences, biology, business.industry, Interferon-alpha, Hepatitis C, Hepatitis C, Chronic, Viral Load, medicine.disease, biology.organism_classification, Recombinant Proteins, 3. Good health, Infectious Diseases, chemistry, 030220 oncology & carcinogenesis, Medicine, Female, Interferons, business, Viral load
Abstract

In chronic hepatitis C virus (HCV) infections, the current standard of care (combination therapy with pegylated alpha interferon (PEG-IFNalpha) and ribavirin) is only effective in around 50% of cases. The aim of the present study was to analyze the relationship between the HCV load and the PEG-IFN concentration during the first week of treatment. Fifteen treatment-naive patients with chronic hepatitis C infection (genotypes 1, 2, 3, and 4) underwent PEG-IFNα-2b/ribavirin combination therapy. Blood samples were collected before the first injection (T(0)) and then at different time points until the next injection a week later. The PEG-IFN concentration and the HCV load were assayed. The serum interferon concentration peaked 2 days after the first injection (mean value for the study population; T(max) = 40.9 hr; C(max) = 490 pg/ml) and a trough in viral load was seen at day 3. The PEG-IFNalpha-2b concentration decreased from day 2 to day 7, enabling a viral rebound in all patients. The change in viral load between day 0 and day 3 differed significantly according to whether the patients were responders at week 12 (Deltalog d(0)/d(3) = 2.729 +/- 1.419 log(10) IU/ml) or not (Deltalog d(0)/d(3) = 1.102 +/- 0.472 log(10) IU/ml). Our results emphasize the potential clinical importance of achieving viral decay immediately after initiation of interferon-ribavirin combination therapy. J. Med. Virol. 82:1640-1646, 2010. 2010 Wiley-Liss, Inc.

Published
2010

16. Estimated protection against COVID-19 based on predicted neutralisation titres from multiple antibody measurements in a longitudinal cohort, France, April 2020 to November 2021.

Author

Woudenberg T, Pinaud L, Garcia L, Tondeur L, Pelleau S, De Thoisy A, Donnadieu F, Backovic M, Attia M, Hozé N, Duru C, Koffi AD, Castelain S, Ungeheuer MN, Fernandes Pellerin S, Planas D, Bruel T, Cauchemez S, Schwartz O, Fontanet A, and White M

Subjects
Humans, Antibodies, Neutralizing, Antibodies, Viral, France epidemiology, Reinfection, SARS-CoV-2, COVID-19 epidemiology
Abstract

BackgroundThe risk of SARS-CoV-2 (re-)infection remains present given waning of vaccine-induced and infection-acquired immunity, and ongoing circulation of new variants.AimTo develop a method that predicts virus neutralisation and disease protection based on variant-specific antibody measurements to SARS-CoV-2 antigens.MethodsTo correlate antibody and neutralisation titres, we collected 304 serum samples from individuals with either vaccine-induced or infection-acquired SARS-CoV-2 immunity. Using the association between antibody and neutralisation titres, we developed a prediction model for SARS-CoV-2-specific neutralisation titres. From predicted neutralising titres, we inferred protection estimates to symptomatic and severe COVID-19 using previously described relationships between neutralisation titres and protection estimates. We estimated population immunity in a French longitudinal cohort of 905 individuals followed from April 2020 to November 2021.ResultsWe demonstrated a strong correlation between anti-SARS-CoV-2 antibodies measured using a low cost high-throughput assay and antibody response capacity to neutralise live virus. Participants with a single vaccination or immunity caused by infection were especially vulnerable to symptomatic or severe COVID-19. While the median reduced risk of COVID-19 from Delta variant infection in participants with three vaccinations was 96% (IQR: 94-98), median reduced risk among participants with infection-acquired immunity was only 42% (IQR: 22-66).ConclusionOur results are consistent with data from vaccine effectiveness studies, indicating the robustness of our approach. Our multiplex serological assay can be readily adapted to study new variants and provides a framework for development of an assay that would include protection estimates.

Published
2023
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17. Ruxolitinib-induced reactivation of cytomegalovirus and Epstein-Barr virus in graft-versus-host disease.

Author

Lebon D, Dujardin A, Caulier A, Joris M, Charbonnier A, Gruson B, Quint M, Castelain S, François C, Lacassagne MN, Guillaume N, Marolleau JP, and Morel P

Subjects
Humans, Cytomegalovirus, Herpesvirus 4, Human, Retrospective Studies, Epstein-Barr Virus Infections complications, Hematopoietic Stem Cell Transplantation adverse effects, Cytomegalovirus Infections complications, Graft vs Host Disease drug therapy, Graft vs Host Disease etiology
Abstract

Objectives: Steroid-refractory graft-versus-host disease (SR-GVHD) is a challenging complication of allogeneic hematopoietic stem cell transplantation, and leads to high morbidity and mortality rates. The orally administered, selective Janus-associated kinase 1/2 inhibitor ruxolitinib gives overall response rates (ORR) of more than 70 % in acute and chronic SR-GVHD. However, several studies have highlighted an elevated risk of cytomegalovirus (CMV) reactivation in patients with ruxolitinib-treated SR-GVHD., Methods: We therefore analyzed risk of CMV and Epstein-Barr virus (EBV) primary infection or reactivation in 57 patients with ruxolitinib-treated GVHD, while taking account of the competing risk (CR) of death prior to the first reactivation., Results: Initiation of ruxolitinib treatment was a significant adverse prognostic factor for the CR of first CMV reactivation (hazard ratio (HR)= 1.747, 95 % confidence interval (CI): 1.33-2.92, p < 0.0001) and first EBV reactivation (HR=2.657, 95 % CI: 1.82-3.87, p < 0.0001) during GVHD. In our cohort of ruxolitinib-treated patients, the ORR (48 % and 58 % for acute and chronic GVHD, respectively) and the toxicity profile (haematological adverse events in 29.8 % of the patients) were similar to the literature values., Conclusion: Given ruxolitinib's efficacy in SR-GVHD, use of this drug should not be limited by the fear of viral reactivation; however, our present results emphasize the importance of monitoring the viral load., Competing Interests: Conflict of interest statement The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Published
2023
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18. Neutralising antibody responses to SARS-CoV-2 omicron among elderly nursing home residents following a booster dose of BNT162b2 vaccine: A community-based, prospective, longitudinal cohort study.

Author

Bruel T, Pinaud L, Tondeur L, Planas D, Staropoli I, Porrot F, Guivel-Benhassine F, Attia M, Pelleau S, Woudenberg T, Duru C, Koffi AD, Castelain S, Fernandes-Pellerin S, Jolly N, De Facci LP, Roux E, Ungeheuer MN, Van Der Werf S, White M, Schwartz O, and Fontanet A

Abstract

Background: The protective immunity against omicron following a BNT162b2 Pfizer booster dose among elderly individuals (ie, those aged >65 years) is not well characterised., Methods: In a community-based, prospective, longitudinal cohort study taking place in France in which 75 residents from three nursing homes were enrolled, we selected 38 residents who had received a two-dose regimen of mRNA vaccine and a booster dose of Pfizer BNT162b2 vaccine. We excluded individuals that did not receive three vaccine doses or did not have available sera samples. We measured anti-S IgG antibodies and neutralisation capacity in sera taken 56 (28-68) and 55 (48-64) days (median (range)) after the 2 nd and 3 rd vaccine doses, respectively. Antibodies targeting the SARS-CoV-2 Spike protein were measured with the S-Flow assay as binding antibody units per milliliter (BAU/mL). Neutralising activities in sera were measured as effective dilution 50% (ED50) with the S-Fuse assay using authentic isolates of delta and omicron BA.1., Findings: Among the 38 elderly individuals recruited to the cohort study between November 23 rd , 2020 and April 29 th , 2021, with median age of 88 (range 72-101) years, 30 (78.95%) had been previously infected with SARS-CoV-2. After three vaccine doses, serum neutralising activity was lower against omicron BA.1 (median ED50 of 774.5, range 15.0-34660.0) than the delta variant (median ED50 of 4972.0, range 213.7-66340.0), and higher among previously infected (ie, convalescent; median ED50 against omicron: 1088.0, range 32.6-34660.0) compared with infection-naive residents (median ED50 against omicron: 188.4, range 15.0-8918.0). During the French omicron wave in December 2021-January 2022, 75% (6/8) of naive residents were infected, compared to 25% (7/30) of convalescent residents ( P =0.0114). Anti-Spike antibody levels and neutralising activity against omicron BA.1 after a third BNT162b2 booster dose were lower in those with breakthrough BA.1 infection ( n =13) compared with those without ( n =25), with a median of 1429.9 (range 670.9-3818.3) BAU/mL vs 2528.3 (range 695.4-8832.0) BAU/mL ( P =0.029) and a median ED50 of 281.1 (range 15.0-2136.0) vs 1376.0 (range 32.6-34660.0) ( P =0.0013), respectively., Interpretation: This study shows that elderly individuals who received three vaccine doses elicit neutralising antibodies against the omicron BA.1 variant of SARS-CoV-2. Elderly individuals who had also been previously infected showed higher neutralising activity compared with naive individuals. Yet, breakthrough infections with omicron occurred. Individuals with breakthrough infections had significantly lower neutralising titers compared to individuals without breakthrough infection. Thus, a fourth dose of vaccine may be useful in the elderly population to increase the level of neutralising antibodies and compensate for waning immunity., Funding: Institut Pasteur, Fondation pour la Recherche Médicale (FRM), European Health Emergency Preparedness and Response Authority (HERA), Agence nationale de recherches sur le sida et les hépatites virales - Maladies Infectieuses Emergentes (ANRS-MIE), Agence nationale de la recherche (ANR), Assistance Publique des Hôpitaux de Paris (AP-HP) and Fondation de France., Competing Interests: SvdW is a member of the Data Safety Monitoring Board of the DISCOVERY trial and the EU-solidact trial, and an associate editor within the Eurosurveillance journal. MW and SP declare a pending patent (US 63/057.471), SvdW declares issued patents (EP1697507, EP1694829, PCT/EP2020055939, US16/809.717 and WO20211176099), and a provisional patent (US63003855). All the other authors declare no competing interests., (© 2022 The Authors.)

Published
2022
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19. Beneficial outcomes and epidemiologics of atypical electrophoretic profiles arising after allogeneic hematopoietic stem cell transplantation for myeloid malignancies.

Author

Hedhli K, Clichet V, Charbonnier A, Castelain S, Galmiche A, Marolleau JP, Boyer T, Caulier A, and Sauzay C

Subjects
Electrophoresis, Humans, Neoplasm Recurrence, Local, Retrospective Studies, Graft vs Host Disease epidemiology, Hematopoietic Stem Cell Transplantation adverse effects
Abstract

Purpose of the Study: Atypical serum protein electrophoresis (SPE) profiles may arise in patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT), but little is known about their clinical significance. Atypical SPE combine either monoclonal and oligoclonal components, suspected on SPE and confirmed by immunofixation. The aim of the study is to analyze the incidence, the etiology and the clinical significance of atypical SPE profiles in patients who received allo-HSCT., Patients and Methods: This retrospective study enrolled 117 patients with myeloid malignancies who received an allo-HSCT between 2012 and 2018. We excluded patients with lymphoid malignancies or multiple myeloma, patients presenting atypical electrophoresis prior to transplantation and patients who died within 100 days post-transplant., Results: Atypical SPE occurred in 42.7% of patients. The cumulative incidence of atypical profiles was significantly higher in patients with acute Graft Versus Host Disease (GVHD, p = 0.019) and in patients with Cytomegalovirus (CMV) reactivation (p = 0.0017). We observed for the first time that atypical SPE profiles mostly occurred in patients transplanted from a CMV+ donor (p = 0.031). CMV reactivation preceded the occurrence of atypical SPE in the majority of patients. We show that atypical SPE delay the relapse of the underlying malignant disease (486 vs 189 days, p = 0.006), and significantly improve overall survival (OS; 33.1 months vs 28.3 months, p = 0.049). In both univariate and multivariate analyzes, the presence of an atypical SPE is the only factor that significantly improves OS., Conclusions: The occurrence of atypical SPE profiles after allo-HSCT may reflect an adapted post-transplant immune response leading to favourable outcomes., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Published
2022
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20. COVID-19 serology in nursing homes and long-term care facilities: prevalence of seroconversion in the Amiens-Picardie University Hospital.

Author

Moyet J, Joseph C, Brochot E, Defouilloy I, Brasseur T, Smarandache C, Boutalha S, Castelain S, Schmit JL, and Bloch F

Abstract

Introduction: Since December 2019, an emerging infectious viral disease triggered by SARS-CoV-2 has caused a global pandemic. Elderly people, being more fragile, are the most affected by the severity and lethality of this disease. The residential care facility for dependent elderly people (Ehpad) and the long-term care facilities at the Amiens University Hospital registered their first COVID-19 cases in February 2020, which lead to the opening of a dedicated COVID-19 unit and aspecific protocol for isolation., Methods: This descriptive study analysed the prevalence of COVID-19 seroconversion within the Ehpad and the long-term care facilities at the Amiens University Hospital. Both this screening test and the nasopharyngeal swab PCRs were used to assess the impact of the COVID-19 epidemic on the residents of the Ehpad and the long-term care facilities., Results: On 15 and 16 June 2020, the serological tests for COVID-19 were positive for 146 (66.1%) of the residents tested. The seroconversion rate was significantly different (p < 0.001) between the Ehpad (88.7%) and the long-term care facility (45.6%)., Discussion: During the epidemic, there was no excess mortality index within the Ehpad and the long-term care facility services of the Amiens University Hospital. Among frail patients, the role of immunosenescence can be evoked to account for the absence of this inflammatory reaction. This study showed that isolating the infected patient in a dedicated unit significantly reduces the risk of seroconversion and contamination compared to isolating them within their own unit.

Published
2021
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21. [Covid-19 serology in nursing home and long-term care: prevalence of seroconversion in the Amiens-Picardie University Hospital].

Author

Moyet J, Joseph C, Brochot E, Defouilloy I, Brasseur T, Smarandache C, Boutalha S, Castelain S, Schmit JL, and Bloch F

Subjects
Aged, COVID-19 epidemiology, COVID-19 immunology, COVID-19 therapy, COVID-19 Serological Testing, Hospitals, Humans, Immunization, Passive, Immunosenescence, Nursing Homes, Prevalence, Reverse Transcriptase Polymerase Chain Reaction, Serologic Tests, COVID-19 Serotherapy, COVID-19 diagnosis, Long-Term Care, SARS-CoV-2 immunology, Seroconversion
Abstract

Since December 2019, an emerging infectious viral disease implicating a coronavirus SARS-CoV-2 has caused a global pandemic. Elderly people, being more fragile, are the most affected by the severity and lethality of this disease. The NH and LTCU of the Amiens University Hospital registered their first Covid-19 cases in February 2020, which lead to the opening of a Covid-19 dedicated unit and of specific protocol for confinement. This descriptive study was analyzing the prevalence of Covid-19 seroconversion within the NH and the LTCU of the Amiens University Hospital. Both this screening test and the nasopharyngeal swab PCRs were in order to assess the impact of the Covid-19 epidemic in NH and LTCU. On June 15th and 16th, the serological tests for Covid-19 were positive for 146 (66.1%) of the residents tested. The seroconversion rate was significantly different (p < 0.001) between the NH (88.7%) and the LTCU (45.6%). During the epidemic, there was no excess mortality index within the NH and LTCU services of the Amiens University Hospital. Among frail patients, the role of immunosenescence can be discussed to account for the absence of this inflammatory reaction. This study showed that isolating the infected patient in a dedicated unit significantly reduces the risk of seroconversion and contamination compared to isolating them within their own unit.

Published
2021
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22. Impact of Human Immunodeficiency Virus Type 1 Minority Variants on the Virus Response to a Rilpivirine-Based First-line Regimen.

Author

Raymond S, Nicot F, Pallier C, Bellecave P, Maillard A, Trabaud MA, Morand-Joubert L, Rodallec A, Amiel C, Mourez T, Bocket L, Beby-Defaux A, Bouvier-Alias M, Lambert-Niclot S, Charpentier C, Malve B, Mirand A, Dina J, Le Guillou-Guillemette H, Marque-Juillet S, Signori-Schmuck A, Barin F, Si-Mohamed A, Avettand Fenoel V, Roussel C, Calvez V, Saune K, Marcelin AG, Rodriguez C, Descamps D, and Izopet J

Subjects
Adult, Drug Resistance, Viral, Female, Genetic Variation, Humans, Male, Mutation, Rilpivirine administration & dosage, Viral Load, HIV Infections drug therapy, HIV Infections virology, HIV-1 drug effects, HIV-1 genetics, Rilpivirine therapeutic use
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 <50 copies/mL at month 6 with continued suppression at month 12. NGS was performed at baseline (retrospectively) on the 454 GS-FLX platform (Roche)., Results: NGS revealed resistance-associated mutations accounting for 1% to <5% of variants in 17.2% of samples, for 5%-20% in 5.7% of samples, and for >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 <250 cells/µL at baseline, a slower decrease in viral load at month 3, and rilpivirine resistance at baseline using the Stanford algorithm with a 20% threshold., Conclusions: Minority resistant variants had no impact on the VR of treatment-naive patients to a rilpivirine-based regimen.

Published
2018
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23. Comparison of Abbott Architect ® , Siemens Immulite ® , and Diasorin Liaison ® for determination of Epstein-Barr virus serological diagnosis.

Author

François C, Segard C, Bouvier M, Stefanski M, Pannier C, Zawadzki P, Roussel C, Hecquet D, Duverlie G, Brochot E, and Castelain S

Subjects
Epstein-Barr Virus Infections virology, Herpesvirus 4, Human isolation & purification, Humans, Immunoglobulin G blood, Immunoglobulin M blood, Retrospective Studies, Sensitivity and Specificity, Virology, Antibodies, Viral blood, Antigens, Viral blood, Epstein-Barr Virus Infections diagnosis, Herpesvirus 4, Human immunology, Immunoassay methods
Abstract

This study compared the performance of 3 automated immunoassays, Architect ® (Abbott), Immulite ® (Siemens) and Liaison ® (Diasorin), for Epstein-Barr virus (EBV) serology. Ninety-one serum samples collected in Amiens University Hospital were analyzed for the presence of Viral Capsid Antigen (VCA) IgG and IgM and Epstein-Barr Nuclear Antigen (EBNA) IgG. The agreement between the 3 assays was calculated for each marker individually and for determination of the EBV profile, based on interpretation of the combination of these 3 EBV markers. Although similar results were obtained with Architect ® and Liaison ® , several discordant results were observed with Immulite ® , particularly for EBNA IgG. A large number of EBNA IgG-positive results were observed, which interfered with interpretation of the EBV profile. In contrast, Immulite ® performed similarly to the 2 other assays for detection of VCA IgM., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Published
2018
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24. Prevalence of HIV-1 drug resistance in treated patients with viral load >50 copies/mL: a 2014 French nationwide study.

Author

Assoumou L, Charpentier C, Recordon-Pinson P, Grudé M, Pallier C, Morand-Joubert L, Fafi-Kremer S, Krivine A, Montes B, Ferré V, Bouvier-Alias M, Plantier JC, Izopet J, Trabaud MA, Yerly S, Dufayard J, Alloui C, Courdavault L, Le Guillou-Guillemette H, Maillard A, Amiel C, Vabret A, Roussel C, Vallet S, Guinard J, Mirand A, Beby-Defaux A, Barin F, Allardet-Servent A, Ait-Namane R, Wirden M, Delaugerre C, Calvez V, Chaix ML, Descamps D, and Reigadas S

Subjects
Adult, Antiretroviral Therapy, Highly Active, Female, France, Genes, Viral, Genotype, HIV Infections blood, HIV Integrase blood, HIV Integrase genetics, HIV Protease blood, HIV Protease genetics, HIV Reverse Transcriptase blood, HIV Reverse Transcriptase genetics, HIV-1 genetics, Humans, Male, Middle Aged, RNA, Viral blood, Reverse Transcriptase Inhibitors therapeutic use, Sequence Analysis, DNA, Treatment Failure, Anti-HIV Agents therapeutic use, Drug Resistance, Multiple, Viral, HIV Infections drug therapy, HIV Infections virology, HIV-1 drug effects, Viral Load
Abstract

Background: Surveillance of HIV-1 resistance in treated patients with a detectable viral load (VL) is important to monitor, in order to assess the risk of spread of resistant viruses and to determine the proportion of patients who need new antiretroviral drugs with minimal cross-resistance., Methods: The HIV-1 protease and reverse transcriptase (RT) and integrase genes were sequenced in plasma samples from 782 consecutive patients on failing antiretroviral regimens, seen in 37 specialized centres in 2014. The genotyping results were interpreted using the ANRS v24 algorithm. Prevalence rates were compared with those obtained during a similar survey conducted in 2009., Results: The protease and RT sequences were obtained in 566 patients, and the integrase sequence in 382 patients. Sequencing was successful in 60%, 78%, 78% and 87% of patients with VLs of 51-200, 201-500, 501-1000 and >1000 copies/mL, respectively. Resistance to at least one antiretroviral drug was detected in 56.3% of samples. Respectively, 3.9%, 8.7%, 1.5% and 3.4% of patients harboured viruses that were resistant to any NRTI, NNRTI, PI and integrase inhibitor (INI). Resistance rates were lower in 2014 than in 2009. Resistance was detected in 48.5% of samples from patients with a VL between 51 and 200 copies/mL., Conclusion: In France in 2014, 90.0% of patients in AIDS care centres were receiving antiretroviral drugs and 12.0% of them had VLs >50 copies/mL. Therefore, this study suggests that 6.7% of treated patients in France might transmit resistant strains. Resistance testing may be warranted in all treated patients with VL > 50 copies/mL., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Published
2017
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25. Positive effect of the hepatitis C virus nonstructural 5A protein on viral multiplication.

Author

Bonte D, François C, Castelain S, Wychowski C, Dubuisson J, Meurs EF, and Duverlie G

Subjects
Apoptosis, Cell Nucleus metabolism, Gene Expression Regulation, Viral, Genes, Reporter, Green Fluorescent Proteins, HeLa Cells, Hepacivirus genetics, Humans, Interleukin-8 genetics, Interleukin-8 metabolism, Luciferases genetics, Luciferases metabolism, Luminescent Proteins metabolism, NF-kappa B genetics, NF-kappa B metabolism, RNA, Messenger analysis, Recombinant Proteins metabolism, Sindbis Virus genetics, Viral Nonstructural Proteins genetics, Viral Proteins genetics, Viral Proteins metabolism, Hepacivirus physiology, Sindbis Virus physiology, Viral Nonstructural Proteins metabolism, Virus Replication
Abstract

Hepatitis C virus infection (HCV), is a major cause of liver disease worldwide, and are frequently resistant to the interferon alpha treatment. The nonstructural (NS) 5A protein of HCV has been proposed to be involved in this resistance. Additional studies have pointed out a role for NS5A in several other cellular interactions as well as an important role of its adaptative mutations in HCV genome replication. However, no infectious system is available to assess the role of NS5A in the HCV life cycle. Thus, we have constructed a recombinant system directly demonstrating for the first time that the expression of NS5A confers a multiplicative advantage to Sindbis virus, a virus close to HCV. This advantage seemed to be related to an anti-apoptotic effect of the NS5A protein. At a later stage, a possible nuclear localization of NS5A was observed, likely due to apoptotic cleavages of this protein. The NS5A protein was also shown to induce the interleukin-8 (IL-8) mRNA and to activate the NF-kappaB pathway independently of the Sindbis virus. Together, our data suggest that the activation of NF-kappaB could lead to the anti-apoptotic activity of NS5A and explain the viral multiplicative advantage conferred by the expression of the NS5A protein.

Published
2004
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