title: Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry.
abstract: Hepatitis C virus (HCV) is a leading cause of cirrhosis and liver cancer worldwide. A better understanding of the viral life cycle, including the mechanisms of entry into host cells, is needed to identify novel therapeutic targets. Although HCV entry requires the CD81 co-receptor, and other host molecules have been implicated, at least one factor critical to this process remains unknown (reviewed in refs 1-3). Using an iterative expression cloning approach we identified claudin-1 (CLDN1), a tight junction component that is highly expressed in the liver, as essential for HCV entry. CLDN1 is required for HCV infection of human hepatoma cell lines and is the first factor to confer susceptibility to HCV when ectopically expressed in non-hepatic cells. Discrete residues within the first extracellular loop (EL1) of CLDN1, but not protein interaction motifs in intracellular domains, are critical for HCV entry. Moreover, antibodies directed against an epitope inserted in the CLDN1 EL1 block HCV infection. The kinetics of this inhibition indicate that CLDN1 acts late in the entry process, after virus binding and interaction with the HCV co-receptor CD81. With CLDN1 we have identified a novel key factor for HCV entry and a new target for antiviral drug development.
authors.affiliation: Center for the Study of Hepatitis C, The Rockefeller University, 1230 York Ave, New York 10021, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Evans
authors.forename: Thomas
authors.initials: T
authors.lastname: von Hahn
authors.forename: Donna M
authors.initials: DM
authors.lastname: Tscherne
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Syder
authors.forename: Maryline
authors.initials: M
authors.lastname: Panis
authors.forename: Benno
authors.initials: B
authors.lastname: Wölk
authors.forename: Theodora
authors.initials: T
authors.lastname: Hatziioannou
authors.forename: Jane A
authors.initials: JA
authors.lastname: McKeating
authors.forename: Paul D
authors.initials: PD
authors.lastname: Bieniasz
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rice
mesh_terms: D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D062445:Claudin-1; D016174:Hepacivirus / Q000378:metabolism / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000821:virology; D008565:Membrane Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D034622:RNA Interference; D011991:Receptors, Virus / Q000378:metabolism*; D013379:Substrate Specificity; D019108:Tight Junctions / Q000737:chemistry / Q000378:metabolism
chemical_list: C568108:CLDN1 protein, human; D062445:Claudin-1; D008565:Membrane Proteins; D011991:Receptors, Virus