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Evans, M. J. et al. Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry. Nature 446, 801-805.OpenURL

Center for the Study of Hepatitis C, The Rockefeller University, 1230 York Ave, New York 10021, USA.
Nature (Impact Factor: 42.35). 05/2007; 446(7137):801-5. DOI: 10.1038/nature05654
Source: PubMed

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.

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Available from: Matthew Evans, Feb 12, 2015
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    • "Hepatitis B and C both promote hepatocarcinogenesis, which is associated with Ecadherin downregulation and Beta-catenin activation. Hepatitis C virus (HCV) enters hepatocytes using the tight junction proteins claudin1 and occludin as co-receptors and a tetraspanin CD81 [136] [137] [138] [139]. Hepatitis B virus (HBV) entry into hepatocytes is dependent upon hepatocyte polarization and it is suggested that the putative viral cell receptor is located in the basolateral membrane, although it's identity is not yet known [140]. "
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    • "Boc: Boceprevir. entry has been firmly established in HuH-7 cells (Evans et al., 2007), an experimental system that has been instrumental in the exploration of the viral infectious cycle (Wakita et al., 2005). In HuH-7 cells exposed to sorafenib, we found that CLDN1 subcellular localization and expression levels were altered. "
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    • "These observations can partially be explained by differences between the second extracellular loops of both CD81 and OCLN from humans and nonpermissive species (Flint et al., 2006; Michta et al., 2010). In contrast, the residues within the first extracellular loop of CLDN1 needed for HCV uptake (Evans et al., 2007) are conserved between mice and humans, explaining the observation that mouse CLDN1 can support viral entry. Although it was originally demonstrated that human but not mouse SCARB1 could bind soluble HCV E2 (Scarselli et al., 2002) both in vitro (Ploss et al., 2009) and in vivo (Dorner et al., 2011, 2013), infection assays demonstrated that mouse and human SCARB1 were equally functional. "
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