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107. Clinical outcomes after treatment with direct antiviral agents: beyond the virological response in patients with previous HCV-related decompensated cirrhosis

Author

Pageaux, G. (Georges-Philippe), Nzinga, C. (Clovis Lusivika), Ganne, N. (Nathalie), Samuel, D. (Didier), Dorival, C. (Céline), Zoulim, F. (Fabien), Cagnot, C. (Carole), Decaens, T. (Thomas), Thabut, D. (Dominique), Asselah, T. (Tarik), Mathurin, P. (Philippe), Habersetzer, F. (Francois), Bronowicki, J. (Jean-Pierre), Guyader, D. (Dominique), Rosa, I. (Isabelle), Leroy, V. (Vincent), Chazouilleres, O. (Olivier), de Ledinghen, V. (Victor), Bourliere, M. (Marc), Causse, X. (Xavier), Cales, P. (Paul), Metivier, S. (Sophie), Loustaud-Ratti, V. (Véronique), Riachi, G. (Ghassan), Alric, L. (Laurent), Gelu-Simeon, M. (Moana), Minello, A. (Anne), Gournay, J. (Jérôme), Geist, C. (Claire), Tran, A. (Albert), Abergel, A. (Armand), Portal, I. (Isabelle), d'Alteroche, L. (Louis), Raffi, F. (François), Fontaine, H. (Hélène), Carrat, F. (Fabrice), Pol, S. (Stanislas), Baumert, Thomas F., Doffoel, M. (Michel), Mutter, C. (Catherine), Simo-Noumbissie, P. (Pauline), Razi, E. (Esma), Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathogénèse et Traitement des Maladies du Foie, Hôpital Paul Brousse-Université Paris-Saclay, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Physiopathologie des Maladies Inflammatoires de l'Intestin, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Interactions Virus-Hôte et Maladies Hépatiques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Virologie, Imagerie Adaptative Diagnostique et Interventionnelle (IADI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service d'Hépato-gastro-entérologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CHU Pontchaillou [Rennes], Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHI Créteil, Biomécanique cellulaire et respiratoire (BCR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Saint-Joseph [Marseille], Centre Hospitalier Régional d'Orléans (CHRO), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Université d'Angers (UA), CHU Toulouse [Toulouse], Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation (IPPRITT), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Nutrition, Inflammation et axe Microbiote-Intestin-Cerveau (ADEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), Service d'Hépato-Gastroentérologie [CHU Rouen], Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Institut des Maladies de l'Appareil Digestif, Université de Nantes (UN), Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), Centre Hospitalier Universitaire de Nice (CHU Nice), CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Institut Pascal (IP), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA)-Institut national polytechnique Clermont Auvergne (INP Clermont Auvergne), Université Clermont Auvergne (UCA)-Université Clermont Auvergne (UCA), Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), 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), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Physiopathologie du système immunitaire (Inserm U1223), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), French ANRS CO22 Hepather Cohort: Delphine Bonnet, Virginie Payssan-Sicart, Chloe Pomes, François Bailly, Marjolaine Beaudoin, Dominique Giboz, Kerstin Hartig-Lavie, Marianne Maynard, Eric Billaud, David Boutoille, Morane Cavellec, Caroline Chevalier, Isabelle Hubert, Pierre Goepfert, Adrien Lannes, Françoise Lunel, Jérôme Boursier, Nathalie Boyer, Nathalie Giuily, Corinne Castelnau, Giovanna Scoazec, Aziza Chibah, Sylvie Keser, Karim Bonardi, Anaïs Vallet-Pichard, Philippe Sogni, Juliette Foucher, Jean-Baptiste Hiriart, Amandine Legendre, Faiza Chermak, Marie Irlès-Depé, Si Nafa Si Ahmed, Christelle Ansaldi, Nisserine Ben Amara, Valérie Oules, Jacqueline Dunette, Rodolphe Anty, Eve Gelsi, Régine Truchi, Elena Luckina, Nadia Messaoudi, Joseph Moussali, Barbara De Dieuleveult, Héloïse Goin, Damien Labarrière, Pascal Potier, Si Nafa Si Ahmed, Véronique Grando-Lemaire, Pierre Nahon, Séverine Brulé, Rym Monard, Caroline Jezequel, Audrey Brener, Anne Laligant, Aline Rabot, Isabelle Renard, Thomas F Baumert, Michel Dofföel, Catherine Mutter, Pauline Simo-Noumbissie, Esma Razi, Hélène Barraud, Mouni Bensenane, Abdelbasset Nani, Sarah Hassani-Nani, Marie-Albertine Bernard, Georges-Philippe Pageaux, Michael Bismuth, Ludovic Caillo, Stéphanie Faure, Marie Pierre Ripault, Christophe Bureau, Sarah Launay, Jean Marie Peron, Marie Angèle Robic, Léa Tarallo, Marine Faure, Bruno Froissart, Marie-Noelle Hilleret, Jean-Pierre Zarski, Odile Goria, Victorien Grard, Hélène Montialoux, Muriel François, Christian Ouedraogo, Christelle Pauleau, Anne Varault, Tony Andreani, Bénédicte Angoulevant, Azeline Chevance, Lawrence Serfaty, Teresa Antonini, Audrey Coilly, Jean-Charles Duclos Vallée, Mariagrazia Tateo, Corinne Bonny, Chanteranne Brigitte, Géraldine Lamblin, Léon Muti, Abdenour Babouri, Virginie Filipe, Camille Barrault, Laurent Costes, Hervé Hagège, Soraya Merbah, Paul Carrier, Maryline Debette-Gratien, Jérémie Jacques, Guillaume Lassailly, Florent Artu, Valérie Canva, Sébastien Dharancy, Alexandre Louvet, Marianne Latournerie, Marc Bardou, Thomas Mouillot, Yannick Bacq, Didier Barbereau, Charlotte Nicolas, Caroline Chevalier, Isabelle Archambeaud, Sarah Habes, Nisserine Ben Amara, Danièle Botta-Fridlund, Eric Saillard, Marie-Josée Lafrance, Carole Cagnot, Alpha Diallo, Lena Wadouachi, Ventzi Petrov-Sanchez, Douae Ammour, Loubna Ayour, Jaouad Benhida, Fabrice Carrat, Frederic Chau, Céline Dorival, Audrey Gilibert, Isabelle Goderel, Warda Hadi, Clovis Luzivika Nzinga, Grégory Pannetier, François Pinot, Odile Stahl, François Téloulé, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and Jonchère, Laurent

Subjects
Liver Cirrhosis, medicine.medical_specialty, Carcinoma, Hepatocellular, Survival, Hepatocellular carcinoma, [SDV]Life Sciences [q-bio], Decompensated cirrhosis, Infectious and parasitic diseases, RC109-216, Hepacivirus, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, complications, drug therapy, Gastroenterology, Antiviral Agents, Virological response, Internal medicine, Medicine, Humans, In patient, business.industry, Hepatitis C virus, Research, Liver Neoplasms, Hepatitis C, [SDV] Life Sciences [q-bio], Sustained virological response, Infectious Diseases, Direst-acting antiviral agents, therapeutic use, business, After treatment
Abstract

Background In HCV-infected patients with advanced liver disease, the direct antiviral agents-associated clinical benefits remain debated. We compared the clinical outcome of patients with a previous history of decompensated cirrhosis following treatment or not with direct antiviral agents from the French ANRS CO22 HEPATHER cohort. Methods We identified HCV patients who had experienced an episode of decompensated cirrhosis. Study outcomes were all-cause mortality, liver-related or non-liver-related deaths, hepatocellular carcinoma, liver transplantation. Secondary study outcomes were sustained virological response and its clinical benefits. Results 559 patients met the identification criteria, of which 483 received direct antiviral agents and 76 remained untreated after inclusion in the cohort. The median follow-up time was 39.7 (IQR: 22.7–51) months. After adjustment for multivariate analysis, exposure to direct antiviral agents was associated with a decrease in all-cause mortality (HR 0.45, 95% CI 0.24–0.84, p = 0.01) and non-liver-related death (HR 0.26, 95% CI 0.08–0.82, p = 0.02), and was not associated with liver-related death, decrease in hepatocellular carcinoma and need for liver transplantation. The sustained virological response was 88%. According to adjusted multivariable analysis, sustained virological response achievement was associated with a decrease in all-cause mortality (HR 0.29, 95% CI 0.15–0.54, p Conclusion Treatment with direct antiviral agents is associated with reduced risk for mortality. The sustained virological response was 88%. Thus, direct antiviral agents treatment should be considered for any patient with HCV-related decompensated cirrhosis. Trial registration: ClinicalTrials.gov registry number: NCT01953458.

Published
2022

114. Abstract P153: Claudin-1 is a therapeutic target for hepatocellular carcinoma

Author

Roehlen, Natascha, primary, Muller, Marion, additional, Cherradi, Sara, additional, Juehling, Frank, additional, Duong, Francois H.T., additional, Almeida, Nuno, additional, Zompo, Fabio Del, additional, Fernandez, Mirian, additional, Riedl, Tobias, additional, Saghire, Hussein El, additional, Saviano, Antonio, additional, Durand, Sarah, additional, Ponsolles, Clara, additional, Oudot, Marine, additional, Felli, Emanuele, additional, Pessaux, Patrick, additional, Davidson, Irwin, additional, Crouchet, Emilie, additional, Laquerriere, Patrick, additional, Heikenwälder, Mathias, additional, Iacone, Roberto, additional, Meyer, Markus, additional, Elson, Greg, additional, Schweighoffer, Tamas, additional, Schuster, Catherine, additional, Mailly, Laurent, additional, Lupberger, Joachim, additional, and Baumert, Thomas F, additional

Published
2021
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115. Direct, indirect and total effect of HIV coinfection on the risk of non-liver-related cancer in hepatitis C virus-infected patients treated by direct-acting antivirals: a mediation analysis: a mediation analysis

Author

Chalouni, M. (Mathieu), Pol, S. (Stanislas), Sogni, P. (Philippe), Fontaine, H. (Helene), Lacombe, K. (Karine), Lacombe, J. (Jean-Marc) M. (M), Esterle, L. (Laure), Dorival, C. (Céline), Bourlière, M. (Marc), Bani-Sadr, F. (Firouzé), de Ledinghen, V. (Victor), Zucman, D. (David), Larrey, D. (Dominique), Salmon, D. (Dominique), Carrat, F. (Fabrice), Wittkop, L. (Linda), Rey, D. (D), Partisani, M., Batard, M.L., Cheneau, C., Priester, M. (M), Bernard-Henry, C., De Mautort, E., Gantner, P. (Pierre), Fafi-Kremer, S. (Samira), Habersetzer, F. (Francois), Baumert, Thomas F., Doffoel, M. (Michel), Mutter, C. (Catherine), Simo-Noumbissie, P. (Pauline), and Razi, E. (Esma)

Subjects
Aucun
Abstract

OBJECTIVES: HIV-coinfected patients experience higher incidences of non-liver-related cancers than HCV-monoinfected patients. Chronic inflammation, immunosuppression, but also higher tobacco or alcohol consumption and metabolic dysregulation could explain this higher risk. We aimed to estimate the direct, indirect and total effects of HIV coinfection on the risk of non-liver-related cancers in HCV participants treated with direct-acting antivirals (DAAs). METHODS: Up to four HCV-monoinfected participants from the ANRS CO22 HEPATHER cohort were matched by age and sex to HIV/HCV-coinfected participants from the ANRS CO13 HEPAVIH cohort. Participants were followed from DAA initiation until the occurrence of a non-liver-related cancer. Counterfactual mediation analysis was carried out to estimate the direct (chronic inflammation and immunosuppression), indirect (tobacco and alcohol consumption and metabolic syndrome) and total effect of HIV coinfection on the risk of non-liver-related cancers. RESULTS: 548 HIV/HCV-coinfected and 2016 monoinfected participants were included. Overall, HIV coinfection was associated with a 3.7-fold [95% confidence interval (CI): 1.7-7.0] higher risk of non-liver-related cancers in HCV participants. This increased risk was explained by significant direct effect [hazard ratio (HR) = 3.4, 95% CI: 1.7-6.6] but not indirect effect (HR = 1.1, 95% CI: 0.8-1.5) of HIV coinfection. CONCLUSIONS: In HCV participants treated with DAAs, the direct effect of HIV coinfection, reflecting chronic inflammation and immunosuppression, was associated with a 3.7-fold higher risk of non-liver-related cancer. By contrast, the indirect effect of HIV coinfection, reflecting higher tobacco and alcohol consumption and metabolic dysregulation, was not significantly associated with the risk of non-liver-related cancers.

Published
2021

116. New Insights into Human Cytomegalovirus pUL52 Structure

Author

Muller, Clotilde, Alain, Sophie, Gourin, Claire, Baumert, Thomas F., Ligat, Gaëtan, Hantz, Sébastien, Anti-infectieux : supports moléculaires des résistances et innovations thérapeutiques (RESINFIT), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-OmégaHealth (ΩHealth), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Service de Bactériologie, Virologie, Hygiène [CHU Limoges], CHU Limoges, Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and univOAK, Archive ouverte

Subjects
[SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Endodeoxyribonucleases, viral targets, viruses, Communication, Amino Acid Motifs, Aucun, Cytomegalovirus, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Acetates, Virus Replication, Microbiology, Antiviral Agents, QR1-502, Viral Proteins, human cytomegalovirus, DNA-packaging, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Cytomegalovirus Infections, terminase, Quinazolines, Humans, pUL52, Conserved Sequence
Abstract

PMC8402748; Human cytomegalovirus (HCMV) can cause serious diseases in immunocompromised patients. Current antiviral inhibitors all target the viral DNA polymerase. They have adverse effects, and prolonged treatment can select for drug resistance mutations. Thus, new drugs targeting other stages of replication are an urgent need. The terminase complex (pUL56-pUL89-pUL51) is highly specific, has no counterpart in the human organism, and thus represents a target of choice for new antivirals development. This complex is required for DNA processing and packaging. pUL52 was shown to be essential for the cleavage of concatemeric HCMV DNA and crucial for viral replication, but its functional domains are not yet identified. Polymorphism analysis was performed by sequencing UL52 from 61 HCMV naive strains and from 14 HCMV strains from patients treated with letermovir. Using sequence alignment and homology modeling, we identified conserved regions and potential functional motifs within the pUL52 sequence. Recombinant viruses were generated with specific serine or alanine substitutions in these putative patterns. Within conserved regions, we identified residues essential for viral replication probably involved in CXXC-like or zinc finger motifs. These results suggest that they are essential for pUL52 structure/function. Thus, these patterns represent potential targets for the development of new antivirals.

Published
2021

118. A Targeted Functional RNA Interference Screen Uncovers Glypican 5 as an Entry Factor for Hepatitis B and D Viruses

Author

Verrier, Eloi R., Colpitts, Che C., Bach, Charlotte, Heydmann, Laura, Weiss, Amélie, Renaud, Mickaël, Durand, Sarah C., Habersetzer, François, Durantel, David, Abou-Jaoudé, Georges, López Ledesma, Maria M., Felmlee, Daniel J., Soumillon, Magali, Croonenborghs, Tom, Pochet, Nathalie, Nassal, Michael, Schuster, Catherine, Brino, Laurent, Sureau, Camille, Zeisel, Mirjam B., and Baumert, Thomas F.

Published
2016
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119. Scavenger receptor class B type I genetic variants associated with disease severity in chronic hepatitis C virus infection.

Author

Arandhara, Victoria L., McClure, Charles Patrick, Tarr, Alexander W., Chappell, Sally, Morgan, Kevin, Baumert, Thomas F., Irving, William L., and Ball, Jonathan K.

Subjects
GENETIC variation, CHRONIC hepatitis C, SINGLE nucleotide polymorphisms, NUTRITION surveys, GENE expression, HEPATIC fibrosis, FIBROSIS
Abstract

Analysis of host genetic polymorphisms is an increasingly important tool for understanding and predicting pathogenesis and treatment response of viral diseases. The gene locus of scavenger receptor class B type I (SR‐BI), encoding a cell entry factor and receptor for hepatitis C virus (HCV), contains several genetic polymorphisms. We applied a probe extension assay to determine the frequency of six single nucleotide polymorphisms (SNPs) within the SR‐BI gene locus in 374 individuals with history of HCV infection. In addition, SR‐BI messenger RNA (mRNA) levels were analyzed in liver biopsy specimens of chronically infected HCV subjects. The rs5888 variant allele T was present at a higher frequency in subjects with advanced fibrosis (χ2, p = 0.016) and after adjusting for age, duration of infection and alcohol intake as confounding factors. Haplotype analysis of SNP frequencies showed that a haplotype consisting of rs61932577 variant allele C and rs5888 variant allele T was associated with an increased risk of advanced liver fibrosis (defined by an Ishak score 4−6) (adjusted odds ratio 2.81; 95% confidence interval 1.06−7.46. p = 0.038). Carriers of the rs5888 variant allele T displayed reduced SR‐BI mRNA expression in liver biopsy specimens. In conclusion the rs5888 polymorphism variant is associated with decreased SR‐BI expression and an increased risk of development of advanced fibrosis in chronic HCV infection. These findings provide further evidence for a role of SR‐BI in HCV pathogenesis and provides a genetic marker for prediction of those infected individuals at greater risk of developing severe disease. [ABSTRACT FROM AUTHOR]

Published
2023
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122. Early Transcriptional Divergence Marks Virus-Specific Primary Human CD8+ T Cells in Chronic versus Acute Infection

Author

Wolski, David, Foote, Peter K., Chen, Diana Y., Lewis-Ximenez, Lia L., Fauvelle, Catherine, Aneja, Jasneet, Walker, Andreas, Tonnerre, Pierre, Torres-Cornejo, Almudena, Kvistad, Daniel, Imam, Sabrina, Waring, Michael T., Tully, Damien C., Allen, Todd M., Chung, Raymond T., Timm, Jörg, Haining, Nicholas W., Kim, Arthur Y., Baumert, Thomas F., and Lauer, Georg M.

Published
2017
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126. Hepatitis B virus compartmentalization and single-cell differentiation in hepatocellular carcinoma

Author

Jühling, Frank, Saviano, Antonio, Ponsolles, Clara, Heydmann, Laura, Crouchet, Emilie, Durand, Sarah C, El Saghire, Houssein, Felli, Emanuele, Lindner, Véronique, Pessaux, Patrick, Pochet, Nathalie, Schuster, Catherine, Verrier, Eloi R, Baumert, Thomas F, Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), L'Institut hospitalo-universitaire de Strasbourg (IHU Strasbourg), Institut National de Recherche en Informatique et en Automatique (Inria)-l'Institut de Recherche contre les Cancers de l'Appareil Digestif (IRCAD)-Les Hôpitaux Universitaires de Strasbourg (HUS)-La Fédération des Crédits Mutuels Centre Est (FCMCE)-L'Association pour la Recherche contre le Cancer (ARC)-La société Karl STORZ, Nouvel Hôpital Civil de Strasbourg, Les Hôpitaux Universitaires de Strasbourg (HUS), Harvard Medical School [Boston] (HMS), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), and ANR-10-LABX-0028,HepSys,Functional genomics of viral hepatitis and liver disease(2010)

Subjects
Adult, Gene Expression Regulation, Viral, Male, Hepatitis B virus, Carcinoma, Hepatocellular, viruses, genetic processes, Hepatitis B, Chronic, Cell Line, Tumor, Humans, natural sciences, Research Articles, Aged, Gene Expression Profiling, Liver Neoplasms, Cell Differentiation, Middle Aged, Viral Load, Cell Transformation, Viral, Hepatitis B, RNA, Viral, Female, Disease Susceptibility, Neoplasm Grading, Single-Cell Analysis, Transcriptome, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Research Article
Abstract

Single-cell RNA-Seq unravels heterogeneity and compartmentalization of both hepatitis B virus and cancer identifying new candidate pathways for viral hepatocarcinogenesis., Chronic hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC) world-wide. The molecular mechanisms of viral hepatocarcinogenesis are still partially understood. Here, we applied two complementary single-cell RNA-sequencing protocols to investigate HBV–HCC host cell interactions at the single cell level of patient-derived HCC. Computational analyses revealed a marked HCC heterogeneity with a robust and significant correlation between HBV reads and cancer cell differentiation. Viral reads significantly correlated with the expression of HBV-dependency factors such as HLF in different tumor compartments. Analyses of virus-induced host responses identified previously undiscovered pathways mediating viral carcinogenesis, such as E2F- and MYC targets as well as adipogenesis. Mapping of fused HBV–host cell transcripts allowed the characterization of integration sites in individual cancer cells. Collectively, single-cell RNA-Seq unravels heterogeneity and compartmentalization of both, virus and cancer identifying new candidate pathways for viral hepatocarcinogenesis. The perturbation of pro-carcinogenic gene expression even at low HBV levels highlights the need of HBV cure to eliminate HCC risk.

Published
2021

128. Influence of gender on cytokine induced depression and treatment

Author

Sarkar, Susanne, primary, Kemper, Jonas, additional, Sarkar, Rahul, additional, Brants, Loni, additional, Friebe, Astrid, additional, Spengler, Ulrich, additional, Schläpfer, Thomas, additional, Reimer, Jens, additional, Buggisch, Peter, additional, Ockenga, Johann, additional, Link, Ralph, additional, Rentrop, Michael, additional, Weidenbach, Hans, additional, Fromm, Gwendolyn, additional, Lieb, Klaus, additional, Baumert, Thomas F., additional, Discher, Thomas, additional, Zeuzem, Stefan, additional, Berg, Thomas, additional, and Schaefer, Martin, additional

Published
2021
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131. Oxidative Stress Triggers Selective tRNA Retrograde Transport in Human Cells during the Integrated Stress Response

Author

Schwenzer, Hagen, Jühling, Frank, Chu, Alexander, Pallett, Laura J., Baumert, Thomas F., Maini, Mala, Fassati, Ariberto, University College of London [London] (UCL), Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nouvel Hôpital Civil de Strasbourg, L'Institut hospitalo-universitaire de Strasbourg (IHU Strasbourg), Institut National de Recherche en Informatique et en Automatique (Inria)-l'Institut de Recherche contre les Cancers de l'Appareil Digestif (IRCAD)-Les Hôpitaux Universitaires de Strasbourg (HUS)-La Fédération des Crédits Mutuels Centre Est (FCMCE)-L'Association pour la Recherche contre le Cancer (ARC)-La société Karl STORZ, and univOAK, Archive ouverte

Subjects
Cytoplasm, Aucun, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Article, RNA Transport, eIF-2 Kinase, RNA, Transfer, Humans, oxidative stress, tRNA, fluorescence in situ hybridization, lcsh:QH301-705.5, Cell Nucleus, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, TOR Serine-Threonine Kinases, nucleus, unfolded protein response, Pkr, retrograde transport, lcsh:Biology (General), Redd1, mTOR, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, HeLa Cells, Signal Transduction, Transcription Factors
Abstract

Summary In eukaryotes, tRNAs are transcribed in the nucleus and exported to the cytosol, where they deliver amino acids to ribosomes for protein translation. This nuclear-cytoplasmic movement was believed to be unidirectional. However, active shuttling of tRNAs, named tRNA retrograde transport, between the cytosol and nucleus has been discovered. This pathway is conserved in eukaryotes, suggesting a fundamental function; however, little is known about its role in human cells. Here we report that, in human cells, oxidative stress triggers tRNA retrograde transport, which is rapid, reversible, and selective for certain tRNA species, mostly with shorter 3′ ends. Retrograde transport of tRNASeC, which promotes translation of selenoproteins required to maintain homeostatic redox levels in cells, is highly efficient. tRNA retrograde transport is regulated by the integrated stress response pathway via the PERK-REDD1-mTOR axis. Thus, we propose that tRNA retrograde transport is part of the cellular response to oxidative stress., Graphical Abstract, Highlights • Oxidative stress triggers nuclear import of cytoplasmic tRNAs • Import is selective for certain tRNAs • Import requires activation of the unfolded protein response and inhibition of mTOR via REDD1 • tRNA nuclear import is a component of the integrated stress response, Schwenzer et. al discovered that oxidative stress induces nuclear import of cytoplasmic tRNAs. The authors found that this pathway is activated during the integrated stress response. tRNA nuclear import was selective to certain tRNA species and may contribute to the changes in protein translation known to protect cells from stress.

Published
2019

139. Nucleic Acid-Induced Signaling in Chronic Viral Liver Disease

Author

Roca Suarez, Armando Andres, Testoni, Barbara, Baumert, Thomas F., Lupberger, Joachim, Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), L'Institut hospitalo-universitaire de Strasbourg (IHU Strasbourg), Institut National de Recherche en Informatique et en Automatique (Inria)-l'Institut de Recherche contre les Cancers de l'Appareil Digestif (IRCAD)-Les Hôpitaux Universitaires de Strasbourg (HUS)-La Fédération des Crédits Mutuels Centre Est (FCMCE)-L'Association pour la Recherche contre le Cancer (ARC)-La société Karl STORZ, Nouvel Hôpital Civil de Strasbourg, Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), and univOAK, Archive ouverte

Subjects
hepatitis C virus, Hepatitis B virus, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Carcinoma, Hepatocellular, Immunology, Liver Neoplasms, Aucun, Review, hepatocellular carcinoma, Hepacivirus, Hepatitis C, Chronic, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, digestive system diseases, Hepatitis B, Chronic, inflammation, viral sensing, DNA, Viral, Immunology and Allergy, Humans, RNA, Viral, signaling, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Signal Transduction
Abstract

PMC7892431; A hallmark for the development and progression of chronic liver diseases is the persistent dysregulation of signaling pathways related to inflammatory responses, which eventually promotes the development of hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The two major etiological agents associated with these complications in immunocompetent patients are hepatitis B virus (HBV) and hepatitis C virus (HCV), accounting for almost 1.4 million liver disease-associated deaths worldwide. Although both differ significantly from the point of their genomes and viral life cycles, they exert not only individual but also common strategies to divert innate antiviral defenses. Multiple virus-modulated pathways implicated in stress and inflammation illustrate how chronic viral hepatitis persistently tweaks host signaling processes with important consequences for liver pathogenesis. The following review aims to summarize the molecular events implicated in the sensing of viral nucleic acids, the mechanisms employed by HBV and HCV to counter these measures and how the dysregulation of these cellular pathways drives the development of chronic liver disease and the progression toward HCC.

Published
2021

141. Hypoxia inducible factors regulate hepatitis B virus replication by activating the basal core promoter

Author

Wing, Peter A.C., primary, Liu, Peter Jianrui, additional, Harris, James M., additional, Magri, Andrea, additional, Michler, Thomas, additional, Zhuang, Xiaodong, additional, Borrmann, Helene, additional, Minisini, Rosalba, additional, Frampton, Nicholas R., additional, Wettengel, Jochen M., additional, Mailly, Laurent, additional, D’Arienzo, Valentina, additional, Riedl, Tobias, additional, Nobre, Luis, additional, Weekes, Michael P., additional, Pirisi, Mario, additional, Heikenwalder, Mathias, additional, Baumert, Thomas F., additional, Hammond, Ester M., additional, Mole, David R., additional, Protzer, Ulrike, additional, Balfe, Peter, additional, and McKeating, Jane A., additional

Published
2021
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143. Similar 5-year HCC occurrence in Tenofovir- and Entecavir-treated HBV chronic infection in the French AFEF/ANRS CO22 Hepather cohort

Author

Pol, Stanislas, Bonnet, Delphine, Payssan-Sicart, Virginie, Pomes, Chloe, Bailly, François, Beaudoin, Marjolaine, Giboz, Dominique, Hartig-Lavie, Kerstin, Maynard, Marianne, Billaud, Eric, Boutoille, David, Cavellec, Morane, Chevalier, Caroline, Hubert, Isabelle, Goepfert, Pierre, Lannes, Adrien, Lunel, François, Boursier, Jérôme, Boyer, Nathalie, Giuily, Nathalie, Castelnau, Corinne, Scoazec, Giovanna, Chibah, Aziza, Keser, Sylvie, Bonardi, Karim, Vallet-Pichard, Anaïs, Sogni, Philippe, Foucher, Juliette, Hiriart, Jean-Baptiste, Legendre, Amandine, Chermak, Faiza, Irlès-Depé, Marie, Ahmed, Si Nafa Si, Ansaldi, Christelle, Amara, Nisserine Ben, Oules, Valérie, Dunette, Jacqueline, Anty, Rodolphe, Gelsi, Eve, Truchi, Régin, Luckina, Elena, Messaoudi, Nadia, Moussali, Joseph, Dieuleveult, Barbara De, Goin, Héloïse, Labarrière, Damien, Potier, Pascal, Grando-Lemaire, Véronique, Nahon, Pierre, Brulé, Séverin, Monard, Rym, Jezequel, Caroline, Brener, Audrey, Laligant, Anne, Rabot, Aline, Renard, Isabelle, Baumert, Thomas F, Dofföel, Michel, Mutter, Catherine, Simo-Noumbissie, Pauline, Razi, Esma, Barraud, Hélène, Bensenane, Mouni, Nani, Abdelbasset, Hassani-Nani, Sarah, Bernard, Marie-Albertine, Pageaux, Georges-Philippe, Bismuth, Michael, Caillo, Ludovic, Faure, Stéphani, Ripault, Marie Pierre, Bureau, Christophe, Launay, Sarah, Peron, Jean Marie, Robic, Marie Angèl, Tarallo, Lé, Faure, Marine, Froissart, Bruno, Hilleret, Marie-Noelle, Zarski, Jean-Pierre, Goria, Odile, Grard, Victorien, E Montialoux, Hélè, François, Muriel, Ouedraogo, Christian, Pauleau, Christelle, Varault, Anne, Andreani, Tony, E Angoulevant, Bénédic, Chevance, Azeline, Serfaty, Lawrence, Antonini, Teresa, Coilly, Audrey, Vallée, Jean-Charles Duclos, Tateo, Mariagrazia, Bonny, Corinne, Brigitte, Chanteranne, Lamblin, Géraldin, Muti, Léo, Babouri, Abdenour, Filipe, Virginie, Barrault, Camille, Costes, Laurent, Merbah, Soraya, Carrier, Paul, Debette-Gratien, Maryline, Jacques, Jérémie, Lassailly, Guillaume, Artu, Florent, Canva, Valérie, Dharancy, Sébastie, Louvet, Alexandre, Latournerie, Marianne, Bardou, Marc, Mouillot, Thomas, Bacq, Yannick, Barbereau, Didier, Nicolas, Charlotte, Archambeaud, Isabelle, Habes, Sarah, Botta-Fridlund, Danièl, Saillard, Eric, Lafrance, Marie-José, Nzinga, Clovis Luzivika, Dorival, Céline, Zoulim, Fabien, Cagnot, Carole, Decaens, Thomas, Thabut, Dominique, Asselah, Tarik, Mathurin, Philippe, Ganne, Nathalie, Samuel, Didier, Habersetzer, Françoi, Bronowicki, Jean-Pierre, Guyader, Dominique, Rosa, Isabelle, Leroy, Vincent, Chazouilleres, Olivier, Ledinghen, Victor De, Bourliere, Marc, Causse, Xavier, Cales, Paul, Metivier, Sophie, Loustaud-Ratti, Véroniqu, Abergel, Armand, Fontaine, Hélène, Carrat, Fabrice, Département d'hépatologie [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie du système immunitaire (Inserm U1223), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)

Subjects
MESH: Antiviral Agents, MESH: Guanine, MESH: Hepatitis B virus, MESH: Humans, MESH: Tenofovir, MESH: Hepatitis B, Chronic, MESH: Liver Neoplasms, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Carcinoma, Hepatocellular, MESH: Prospective Studies, MESH: Treatment Outcome
Abstract

International audience; Background: Chronic hepatitis B virus (HBV) infection results in a high risk of cirrhosis and its complications, cirrhosis decompensation (DC), hepatocellular carcinoma (HCC), liver transplantation (LT), death or any of these outcomes (composite endpoint [CE]). Nucleos(t)ide analogues (NUCs) such as tenofovir or entecavir are associated with a reduction in these complications.Aim: To compare the impact of tenofovir and entecavir on these outcomes in patients treated for HBV infection and included in the prospective Hepather cohort.Methods: All patients with HBV infection who had received tenofovir or entecavir for more than 6 months at or after entry in the ANRS CO22 cohort were selected. Patients with HDV and HCV co-infection or prior liver event were excluded. Incidence rates of events were compared using inverse probability of treatment weighting (IPW).Results: The cohort included 1800 patients (986 tenofovir and 814 entecavir). Median follow-up was 4.2 years. The incidences of HCC, DC, LT, ACD, LRD and CE were not different between tenofovir- (1.8 (0.9; 3.2), 0.6 (0.2; 1.6), 0.2 (0.0; 0.8), 1.7 (0.8; 3.0), 0.8 (0.2, 1.8) and 4.1 (3.0; 5.4) per 1000 person-years) and entecavir-treated patients (1.6 (0.7; 3.0), 0.7 (0.2; 1.8), 0.2 (0.0; 1.0), 3.0 (1.7, 4.8), 0.5 (0.1; 1.5) and 5.0 (3.3; 7.2)) per 1000 person-years, respectively.Conclusion: The risk of liver-related events or death was not different between tenofovir- and entecavir-treated patients in this large prospective cohort of predominantly non-cirrhotic French patients.Trial registration number: NCT019553458.

Published
2021

144. Liver Abnormalities after Elimination of HCV Infection: Persistent Epigenetic and Immunological Perturbations Post-Cure: Persistent Epigenetic and Immunological Perturbations Post-Cure

Author

Polyak, S. (Stephen) J. (J), Crispe, I. (I) N. (N), and Baumert, Thomas F.

Subjects
Aucun, Sciences du Vivant [q-bio]/Médecine humaine et pathologie
Abstract

Chronic hepatitis C (CHC) is a major cause of hepatocellular carcinoma (HCC) worldwide. While directly acting antiviral (DAA) drugs are now able to cure virtually all hepatitis C virus (HCV) infections, even in subjects with advanced liver disease, what happens to the liver and progression of the disease after DAA-induced cure of viremia is only beginning to emerge. Several large-scale clinical studies in different patient populations have shown that patients with advanced liver disease maintain a risk for developing HCC even when the original instigator, the virus, is eliminated by DAAs. Here we review emerging studies derived from multiple, complementary experimental systems involving patient liver tissues, human liver cell cultures, human liver slice cultures, and animal models, showing that HCV infection induces epigenetic, signaling, and gene expression changes in the liver associated with altered hepatic innate immunity and liver cancer risk. Of critical importance is the fact that these virus-induced abnormalities persist after DAA cure of HCV. These nascent findings portend the discovery of pathways involved in post-HCV immunopathogenesis, which may be clinically actionable targets for more comprehensive care of DAA-cured individuals.

Published
2021

145. Structures and Divergent Mechanisms in Capsid Maturation and Stabilization Following Genome Packaging of Human Cytomegalovirus and Herpesviruses

Author

Muller, Clotilde, Alain, Sophie, Baumert, Thomas F., Ligat, Gaëtan, Hantz, Sébastien, univOAK, Archive ouverte, Anti-infectieux : supports moléculaires des résistances et innovations thérapeutiques (RESINFIT), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), and Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
[SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, herpesviruses, DNA packaging, viruses, Review, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, therapeutic targets, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, human cytomegalovirus, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, lcsh:Q, capsid maturation, lcsh:Science
Abstract

Herpesviruses are the causative agents of several diseases. Infections are generally mild or asymptomatic in immunocompetent individuals. In contrast, herpesvirus infections continue to contribute to significant morbidity and mortality in immunocompromised patients. Few drugs are available for the treatment of human herpesvirus infections, mainly targeting the viral DNA polymerase. Moreover, no successful therapeutic options are available for the Epstein-Barr virus or human herpesvirus 8. Most licensed drugs share the same mechanism of action of targeting the viral polymerase and thus blocking DNA polymerization. Resistances to antiviral drugs have been observed for human cytomegalovirus, herpes simplex virus and varicella-zoster virus. A new terminase inhibitor, letermovir, recently proved effective against human cytomegalovirus. However, the letermovir has no significant activity against other herpesviruses. New antivirals targeting other replication steps, such as capsid maturation or DNA packaging, and inducing fewer adverse effects are therefore needed. Targeting capsid assembly or DNA packaging provides additional options for the development of new drugs. In this review, we summarize recent findings on capsid assembly and DNA packaging. We also described what is known about the structure and function of capsid and terminase proteins to identify novels targets for the development of new therapeutic options.

Published
2020

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

Author

Lupberger, Joachim, Zeisel, Mirjam B., Xiao, Fei, Thumann, Christine, Fofana, Isabel, Zona, Laetitia, Davis, Christopher, Mee, Christopher J., Turek, Marine, Gorke, Sebastian, Royer, Cathy, Fischer, Benoit, Zahid, Muhammad N., Lavillette, Dimitri, Fresquet, Judith, Cosset, Francois-Loic, Rothenberg, S. Michael, Pietschmann, Thomas, Patel, Arvind H., Pessaux, Patrick, Doffoel, Michel, Raffelsberger, Wolfgang, Poch, Olivier, McKeating, Jane A., Brino, Laurent, and Baumert, Thomas F.

Subjects
Ephrin A -- Physiological aspects, Antiviral agents -- Research, Hepatitis C -- Care and treatment -- Patient outcomes -- Physiological aspects, Biological sciences, Health
Abstract

Hepatitis C virus (HCV) is a major cause of liver disease, but therapeutic options are limited and there are no prevention strategies. Viral entry is the first step of infection and requires the cooperative interaction of several host cell factors. Using a functional RNAi kinase screen, we identified epidermal growth factor receptor and ephrin receptor A2 as host cofactors for HCV entry. Blocking receptor kinase activity by approved inhibitors broadly impaired infection by all major HCV genotypes and viral escape variants in cell culture and in a human liver chimeric mouse model in vivo. The identified receptor tyrosine kinases (RTKs) mediate HCV entry by regulating CD81-claudin-1 co-receptor associations and viral glycoprotein-- dependent membrane fusion. These results identify RTKs as previously unknown HCV entry cofactors and show that tyrosine kinase inhibitors have substantial antiviral activity. Inhibition of RTK function may constitute a new approach for prevention and treatment of HCV infection., HCV is a major cause of liver cirrhosis and hepatocellular carcinoma. Current antiviral treatment is limited by drug resistance, toxicity and high costs (1). Although newly developed antiviral substances targeting [...]

Published
2011
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