title: Role of hypervariable region 1 for the interplay of hepatitis C virus with entry factors and lipoproteins.
abstract: Hepatitis C virus (HCV) particles associate with lipoproteins and infect cells by using at least four cell entry factors. These factors include scavenger receptor class B type I (SR-BI), CD81, claudin 1 (CLDN1), and occludin (OCLN). Little is known about specific functions of individual host factors during HCV cell entry and viral domains that mediate interactions with these factors. Hypervariable region 1 (HVR1) within viral envelope protein 2 (E2) is involved in the usage of SR-BI and conceals the viral CD81 binding site. Moreover, deletion of this domain alters the density of virions. We compared lipoprotein interaction, surface attachment, receptor usage, and cell entry between wild-type HCV and a viral mutant lacking this domain. Deletion of HVR1 did not affect CD81, CLDN1, and OCLN usage. However, unlike wild-type HCV, HVR1-deleted viruses were not neutralized by antibodies and small molecules targeting SR-BI. Nevertheless, modulation of SR-BI cell surface expression altered the infection efficiencies of both viruses to similar levels. Analysis of affinity-purified virions revealed comparable levels of apolipoprotein E (ApoE) incorporation into viruses with or without HVR1. However, ApoE incorporated into these viruses was differentially recognized by ApoE-specific antibodies. Thus, SR-BI has at least two functions during cell entry. One of them can be neutralized by SR-BI-targeting molecules, and it is critical only for wild-type HCV. The other one is important for both viruses but apparently is not inactivated by the SR-BI binding antibodies and small molecules evaluated here. In addition, HVR1 modulates the conformation and/or epitope exposure of virus particle-associated ApoE.
  
  
  OBJECTIVE
  HCV cell entry is SR-BI dependent irrespective of the presence or absence of HVR1. Moreover, this domain modulates the properties of ApoE on the surface of virus particles. These findings have implications for the development of SR-BI-targeting antivirals. Furthermore, these findings highlight separable functions of SR-BI during HCV cell entry and reveal a novel role of HVR1 for the properties of virus-associated lipoproteins.
authors.affiliation: Division of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Medical School Hannover (MHH) and Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Bankwitz
authors.affiliation: Division of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Medical School Hannover (MHH) and Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Vieyres
authors.affiliation: Division of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Medical School Hannover (MHH) and Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Hueging
authors.affiliation: Division of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Medical School Hannover (MHH) and Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Bitzegeio
authors.affiliation: Division of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Medical School Hannover (MHH) and Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
authors.forename: Mandy
authors.initials: M
authors.lastname: Doepke
authors.affiliation: Division of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Medical School Hannover (MHH) and Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Chhatwal
authors.affiliation: Division of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Medical School Hannover (MHH) and Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Haid
authors.affiliation: King's College London School of Medicine, Division of Immunology, Infection and Inflammatory Disease, Department of Infectious Diseases, London, United Kingdom Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York, USA.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Catanese
authors.affiliation: Inserm, U1110, Strasbourg, France Université de Strasbourg, Strasbourg, France.
authors.forename: Mirjam B
authors.initials: MB
authors.lastname: Zeisel
authors.affiliation: CEINGE, Naples, Italy Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Nicosia
authors.affiliation: Inserm, U1110, Strasbourg, France Université de Strasbourg, Strasbourg, France.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Baumert
authors.affiliation: Institute for Medical Informatics and Biometry, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Kaderali
authors.affiliation: Division of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Medical School Hannover (MHH) and Helmholtz Centre for Infection Research (HZI), Hannover, Germany thomas.pietschmann@twincore.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pietschmann
mesh_terms: D002460:Cell Line; D062445:Claudin-1 / Q000378:metabolism*; D017353:Gene Deletion; D016174:Hepacivirus / Q000502:physiology*; D022781:Hepatocytes / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism; D062793:Occludin / Q000378:metabolism*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D051122:Scavenger Receptors, Class B / Q000378:metabolism*; D060225:Tetraspanin 28 / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D053586:Virus Internalization
chemical_list: C554798:CD81 protein, human; C568108:CLDN1 protein, human; D062445:Claudin-1; C400562:HVR1 protein, Hepatitis C virus; D008074:Lipoproteins; C568985:OCLN protein, human; D062793:Occludin; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D060225:Tetraspanin 28; D014764:Viral Proteins