title: Hepatitis C virus induces epidermal growth factor receptor activation via CD81 binding for viral internalization and entry.
abstract: While epidermal growth factor receptor (EGFR) has been shown to be important in the entry process for multiple viruses, including hepatitis C virus (HCV), the molecular mechanisms by which EGFR facilitates HCV entry are not well understood. Using the infectious cell culture HCV model (HCVcc), we demonstrate that the binding of HCVcc particles to human hepatocyte cells induces EGFR activation that is dependent on interactions between HCV and CD81 but not claudin 1. EGFR activation can also be induced by antibody mediated cross-linking of CD81. In addition, EGFR ligands that enhance the kinetics of HCV entry induce EGFR internalization and colocalization with CD81. While EGFR kinase inhibitors inhibit HCV infection primarily by preventing EGFR endocytosis, antibodies that block EGFR ligand binding or inhibitors of EGFR downstream signaling have no effect on HCV entry. These data demonstrate that EGFR internalization is critical for HCV entry and identify a hitherto-unknown association between CD81 and EGFR.
authors.affiliation: Departments of Infectious Diseases, Genentech, South San Francisco, California, USA.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Diao
authors.forename: Homer
authors.initials: H
authors.lastname: Pantua
authors.forename: Hai
authors.initials: H
authors.lastname: Ngu
authors.forename: Laszlo
authors.initials: L
authors.lastname: Komuves
authors.forename: Lauri
authors.initials: L
authors.lastname: Diehl
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schaefer
authors.forename: Sharookh B
authors.initials: SB
authors.lastname: Kapadia
mesh_terms: D045744:Cell Line, Tumor; D062445:Claudin-1 / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016174:Hepacivirus / Q000378:metabolism*; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D012367:RNA, Viral; D060225:Tetraspanin 28 / Q000378:metabolism*; D053586:Virus Internalization
chemical_list: D062445:Claudin-1; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D012367:RNA, Viral; D060225:Tetraspanin 28; D066246:ErbB Receptors