title: Apolipoprotein E Mediates Evasion From Hepatitis C Virus Neutralizing Antibodies.
abstract: OBJECTIVE
  Efforts to develop an effective vaccine against hepatitis C virus (HCV) have been hindered by the propensity of the virus to evade host immune responses. HCV particles in serum and in cell culture associate with lipoproteins, which contribute to viral entry. Lipoprotein association has also been proposed to mediate viral evasion of the humoral immune response, though the mechanisms are poorly defined.
  
  
  METHODS
  We used small interfering RNAs to reduce levels of apolipoprotein E (apoE) in cell culture-derived HCV-producing Huh7.5-derived hepatoma cells and confirmed its depletion by immunoblot analyses of purified viral particles. Before infection of naïve hepatoma cells, we exposed cell culture-derived HCV strains of different genotypes, subtypes, and variants to serum and polyclonal and monoclonal antibodies isolated from patients with chronic HCV infection. We analyzed the interaction of apoE with viral envelope glycoprotein E2 and HCV virions by immunoprecipitation.
  
  
  RESULTS
  Through loss-of-function studies on patient-derived HCV variants of several genotypes and subtypes, we found that the HCV particle apoE allows the virus to avoid neutralization by patient-derived antibodies. Functional studies with human monoclonal antiviral antibodies showed that conformational epitopes of envelope glycoprotein E2 domains B and C were exposed after depletion of apoE. The level and conformation of virion-associated apoE affected the ability of the virus to escape neutralization by antibodies.
  
  
  CONCLUSIONS
  In cell-infection studies, we found that HCV-associated apoE helps the virus avoid neutralization by antibodies against HCV isolated from chronically infected patients. This method of immune evasion poses a challenge for the development of HCV vaccines.
authors.affiliation: Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Université de Strasbourg, Strasbourg, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Fauvelle
authors.affiliation: Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Université de Strasbourg, Strasbourg, France; University of Plymouth, Centre for Biomedical Research, Plymouth, UK.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Felmlee
authors.affiliation: Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Université de Strasbourg, Strasbourg, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Crouchet
authors.affiliation: Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany.
authors.forename: JiYoung
authors.initials: J
authors.lastname: Lee
authors.affiliation: Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Université de Strasbourg, Strasbourg, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Heydmann
authors.affiliation: Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Université de Strasbourg, Strasbourg, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lefèvre
authors.affiliation: MRC, University of Glasgow, Centre for Virus Research, Glasgow, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Magri
authors.affiliation: Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany.
authors.forename: Marie-Sophie
authors.initials: MS
authors.lastname: Hiet
authors.affiliation: Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Université de Strasbourg, Strasbourg, France.
authors.forename: Isabel
authors.initials: I
authors.lastname: Fofana
authors.affiliation: Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Université de Strasbourg, Strasbourg, France; Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors.forename: François
authors.initials: F
authors.lastname: Habersetzer
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, California.
authors.forename: Steven K H
authors.initials: SK
authors.lastname: Foung
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors.forename: Ross
authors.initials: R
authors.lastname: Milne
authors.affiliation: MRC, University of Glasgow, Centre for Virus Research, Glasgow, UK.
authors.forename: Arvind H
authors.initials: AH
authors.lastname: Patel
authors.affiliation: Center for Vaccinology, Ghent University, Ghent University Hospital, Ghent, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Vercauteren
authors.affiliation: Center for Vaccinology, Ghent University, Ghent University Hospital, Ghent, Belgium.
authors.forename: Philip
authors.initials: P
authors.lastname: Meuleman
authors.affiliation: Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Université de Strasbourg, Strasbourg, France.
authors.forename: Mirjam B
authors.initials: MB
authors.lastname: Zeisel
authors.affiliation: Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Bartenschlager
authors.affiliation: Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Université de Strasbourg, Strasbourg, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Schuster
authors.affiliation: Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Université de Strasbourg, Strasbourg, France; Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France. Electronic address: Thomas.Baumert@unistra.fr.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Baumert
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology*; D001057:Apolipoproteins E / Q000378:metabolism*; D002478:Cells, Cultured; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D006526:Hepatitis C / Q000097:blood; D018937:Hepatitis C Antibodies / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology; D006801:Humans; D018709:Statistics, Nonparametric; D014759:Viral Envelope Proteins / Q000276:immunology / Q000378:metabolism; D053586:Virus Internalization
chemical_list: D057134:Antibodies, Neutralizing; D001057:Apolipoproteins E; D018937:Hepatitis C Antibodies; D014759:Viral Envelope Proteins
keywords: Lipid; Lipoviral Particle; Vaccination; Viral Escape