title: Mutations that alter use of hepatitis C virus cell entry factors mediate escape from neutralizing antibodies.
abstract: OBJECTIVE
  The development of vaccines and other strategies to prevent hepatitis C virus (HCV) infection is limited by rapid viral evasion. HCV entry is the first step of infection; this process involves several viral and host factors and is targeted by host-neutralizing responses. Although the roles of host factors in HCV entry have been well characterized, their involvement in evasion of immune responses is poorly understood. We used acute infection of liver graft as a model to investigate the molecular mechanisms of viral evasion.
  
  
  METHODS
  We studied factors that contribute to evasion of host immune responses using patient-derived antibodies, HCV pseudoparticles, and cell culture-derived HCV that express viral envelopes from patients who have undergone liver transplantation. These viruses were used to infect hepatoma cell lines that express different levels of HCV entry factors.
  
  
  RESULTS
  By using reverse genetic analyses, we identified altered use of host-cell entry factors as a mechanism by which HCV evades host immune responses. Mutations that alter use of the CD81 receptor also allowed the virus to escape neutralizing antibodies. Kinetic studies showed that these mutations affect virus-antibody interactions during postbinding steps of the HCV entry process. Functional studies with a large panel of patient-derived antibodies showed that this mechanism mediates viral escape, leading to persistent infection in general.
  
  
  CONCLUSIONS
  We identified a mechanism by which HCV evades host immune responses, in which use of cell entry factors evolves with escape from neutralizing antibodies. These findings advance our understanding of the pathogenesis of HCV infection and might be used to develop antiviral strategies and vaccines.
authors.affiliation: Inserm, U748, Strasbourg, France.|Université de Strasbourg, Strasbourg, France.
authors.forename: Isabel
authors.initials: I
authors.lastname: Fofana
authors.affiliation: Inserm, U748, Strasbourg, France.|Université de Strasbourg, Strasbourg, France.|Laboratoire de Virologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Samira
authors.initials: S
authors.lastname: Fafi-Kremer
authors.affiliation: Inserm, U748, Strasbourg, France.|Université de Strasbourg, Strasbourg, France.
authors.forename: Patric
authors.initials: P
authors.lastname: Carolla
authors.affiliation: Inserm, U748, Strasbourg, France.|Université de Strasbourg, Strasbourg, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Fauvelle
authors.affiliation: Inserm, U748, Strasbourg, France.|Université de Strasbourg, Strasbourg, France.
authors.forename: Muhammad Nauman
authors.initials: MN
authors.lastname: Zahid
authors.affiliation: Inserm, U748, Strasbourg, France.|Université de Strasbourg, Strasbourg, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Turek
authors.affiliation: Inserm, U748, Strasbourg, France.|Université de Strasbourg, Strasbourg, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Heydmann
authors.affiliation: Inserm, U748, Strasbourg, France.|Université de Strasbourg, Strasbourg, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Cury
authors.affiliation: Bases Moléculaires et Structurales des Systèmes Infectieux, UMR 5086, Centre National de la Recherche Scientifique, Université de Lyon, Institut de Biologie et Chimie des Proteines, Lyon, France.
authors.forename: Juliette
authors.initials: J
authors.lastname: Hayer
authors.affiliation: Bases Moléculaires et Structurales des Systèmes Infectieux, UMR 5086, Centre National de la Recherche Scientifique, Université de Lyon, Institut de Biologie et Chimie des Proteines, Lyon, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Combet
authors.affiliation: Université de Lyon, Université Claude Bernard Lyon1, IFR 128, Inserm U758; Ecole Normale Supérieure de Lyon, 69364 Lyon, France.
authors.forename: François-Loïc
authors.initials: FL
authors.lastname: Cosset
authors.affiliation: Division of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pietschmann
authors.affiliation: The Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany.
authors.forename: Marie-Sophie
authors.initials: MS
authors.lastname: Hiet
authors.affiliation: The Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Bartenschlager
authors.affiliation: Inserm, U748, Strasbourg, France.|Université de Strasbourg, Strasbourg, France.|Pôle Hepato-Digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: François
authors.initials: F
authors.lastname: Habersetzer
authors.affiliation: Inserm, U748, Strasbourg, France.|Université de Strasbourg, Strasbourg, France.|Pôle Hepato-Digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Doffoël
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California.
authors.forename: Zhen-Yong
authors.initials: ZY
authors.lastname: Keck
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California.
authors.forename: Steven K H
authors.initials: SKH
authors.lastname: Foung
authors.affiliation: Inserm, U748, Strasbourg, France.|Université de Strasbourg, Strasbourg, France.
authors.forename: Mirjam B
authors.initials: MB
authors.lastname: Zeisel
authors.affiliation: Inserm, U748, Strasbourg, France.|Université de Strasbourg, Strasbourg, France.|Laboratoire de Virologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Stoll-Keller
authors.affiliation: Inserm, U748, Strasbourg, France.|Université de Strasbourg, Strasbourg, France.|Pôle Hepato-Digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Baumert
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology*; D045744:Cell Line, Tumor; D016174:Hepacivirus / Q000235:genetics* / Q000276:immunology; D006526:Hepatitis C / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008297:Male; D009154:Mutation; D019737:Transplants / Q000821:virology; D053586:Virus Internalization
chemical_list: D057134:Antibodies, Neutralizing