title: Claudin-6 and Occludin Natural Variants Found in a Patient Highly Exposed but Not Infected with Hepatitis C Virus (HCV) Do Not Confer HCV Resistance In Vitro.
abstract: The clinical course of Hepatitis C Virus (HCV) infection is highly variable between infected individual hosts: up to 80% of acutely HCV infected patients develop a chronic infection while 20% clear infection spontaneously. Spontaneous clearance of HCV infection can be predicted by several factors, including symptomatic acute infection, favorable IFNL3 polymorphisms and gender. In our study, we explored the possibility that variants in HCV cell entry factors might be involved in resistance to HCV infection. In a same case patient highly exposed but not infected by HCV, we previously identified one mutation in claudin-6 (CLDN6) and a rare variant in occludin (OCLN), two tight junction proteins involved in HCV entry into hepatocytes. Here, we conducted an extensive functional study to characterize the ability of these two natural variants to prevent HCV entry. We used lentiviral vectors to express Wildtype or mutated CLDN6 and OCLN in different cell lines and primary human hepatocytes. HCV infection was then investigated using cell culture produced HCV particles (HCVcc) as well as HCV pseudoparticles (HCVpp) expressing envelope proteins from different genotypes. Our results show that variants of CLDN6 and OCLN expressed separately or in combination did not affect HCV infection nor cell-to-cell transmission. Hence, our study highlights the complexity of HCV resistance mechanisms supporting the fact that this process probably not primarily involves HCV entry factors and that other unknown host factors may be implicated.
authors.affiliation: Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-CIIL-Centre d'Infection et d'Immunité de Lille, F-59000 Lille, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Fénéant
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Unité Fonctionnelle de Thérapeutique en Immuno-Infectiologie, Hôpital Universitaire Hôtel Dieu, Paris, France.|Université Paris Descartes, EA 7327, Faculté de Médecine site Necker, Paris, France.
authors.forename: Jade
authors.initials: J
authors.lastname: Ghosn
authors.affiliation: Univ Paris Sud, Faculté de Médecine, Hôpitaux Universitaires Paris Sud, Le Kremlin-Bicêtre and Inserm-U1193, Hôpital Paul Brousse, F-94800 Villejuif, France.
authors.forename: Baptiste
authors.initials: B
authors.lastname: Fouquet
authors.affiliation: Virology Department, Amiens University Hospital, Amiens, France.
authors.forename: François
authors.initials: F
authors.lastname: Helle
authors.affiliation: Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-CIIL-Centre d'Infection et d'Immunité de Lille, F-59000 Lille, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Belouzard
authors.affiliation: Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-CIIL-Centre d'Infection et d'Immunité de Lille, F-59000 Lille, France.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Vausselin
authors.affiliation: Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-CIIL-Centre d'Infection et d'Immunité de Lille, F-59000 Lille, France.
authors.forename: Karin
authors.initials: K
authors.lastname: Séron
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Service de Médecine Interne et Maladies Infectieuses, Centre Hospitalier Universitaire de Bicêtre, Le Kremlin-Bicêtre, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Delfraissy
authors.affiliation: Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-CIIL-Centre d'Infection et d'Immunité de Lille, F-59000 Lille, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Dubuisson
authors.affiliation: Univ Paris Sud, Faculté de Médecine, Hôpitaux Universitaires Paris Sud, Le Kremlin-Bicêtre and Inserm-U1193, Hôpital Paul Brousse, F-94800 Villejuif, France.
authors.forename: Micheline
authors.initials: M
authors.lastname: Misrahi
authors.affiliation: Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-CIIL-Centre d'Infection et d'Immunité de Lille, F-59000 Lille, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Cocquerel
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000378:metabolism / Q000821:virology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D057167:Claudins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D060467:Disease Resistance / Q000235:genetics / Q000276:immunology; D005434:Flow Cytometry; D057809:HEK293 Cells; D056945:Hep G2 Cells; D016174:Hepacivirus / Q000276:immunology* / Q000502:physiology; D006526:Hepatitis C / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D008113:Liver Neoplasms / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008856:Microscopy, Fluorescence; D009154:Mutation / Q000276:immunology; D062793:Occludin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014771:Virion / Q000276:immunology / Q000502:physiology
chemical_list: D057167:Claudins; D062793:Occludin; C122101:claudin 6