title: EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy.
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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U748, Strasbourg, France.
authors.forename: Joachim
authors.initials: J
authors.lastname: Lupberger
authors.forename: Mirjam B
authors.initials: MB
authors.lastname: Zeisel
authors.forename: Fei
authors.initials: F
authors.lastname: Xiao
authors.forename: Christine
authors.initials: C
authors.lastname: Thumann
authors.forename: Isabel
authors.initials: I
authors.lastname: Fofana
authors.forename: Laetitia
authors.initials: L
authors.lastname: Zona
authors.forename: Christopher
authors.initials: C
authors.lastname: Davis
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Mee
authors.forename: Marine
authors.initials: M
authors.lastname: Turek
authors.forename: Sebastian
authors.initials: S
authors.lastname: Gorke
authors.forename: Cathy
authors.initials: C
authors.lastname: Royer
authors.forename: Benoit
authors.initials: B
authors.lastname: Fischer
authors.forename: Muhammad N
authors.initials: MN
authors.lastname: Zahid
authors.forename: Dimitri
authors.initials: D
authors.lastname: Lavillette
authors.forename: Judith
authors.initials: J
authors.lastname: Fresquet
authors.forename: François-Loïc
authors.initials: FL
authors.lastname: Cosset
authors.forename: S Michael
authors.initials: SM
authors.lastname: Rothenberg
authors.forename: Thomas
authors.initials: T
authors.lastname: Pietschmann
authors.forename: Arvind H
authors.initials: AH
authors.lastname: Patel
authors.forename: Patrick
authors.initials: P
authors.lastname: Pessaux
authors.forename: Michel
authors.initials: M
authors.lastname: Doffoël
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Raffelsberger
authors.forename: Olivier
authors.initials: O
authors.lastname: Poch
authors.forename: Jane A
authors.initials: JA
authors.lastname: McKeating
authors.forename: Laurent
authors.initials: L
authors.lastname: Brino
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Baumert
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D000998:Antiviral Agents / Q000494:pharmacology; D001483:Base Sequence; D002460:Cell Line; D062445:Claudin-1; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000069347:Erlotinib Hydrochloride; D016174:Hepacivirus / Q000187:drug effects / Q000502:physiology*; D006526:Hepatitis C / Q000503:physiopathology* / Q000517:prevention & control / Q000628:therapy / Q000821:virology*; D054884:Host-Pathogen Interactions / Q000502:physiology; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D036104:Receptor, EphA2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D060225:Tetraspanin 28; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D015703:Antigens, CD; D000998:Antiviral Agents; C554798:CD81 protein, human; C568108:CLDN1 protein, human; C554799:Cd81 protein, mouse; D062445:Claudin-1; C568113:Cldn1 protein, mouse; D008024:Ligands; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D034741:RNA, Small Interfering; D060225:Tetraspanin 28; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D036104:Receptor, EphA2