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.

Download full-text


Available from: Matthew Evans, Feb 12, 2015
1 Follower
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatocytes form a crucially important cell layer that separates sinusoidal blood from the canalicular bile. They have a uniquely organized polarity with a basal membrane facing liver sinusoidal endothelial cells, while one or more apical poles can contribute to several bile canaliculi jointly with the directly opposing hepatocytes. Establishment and maintenance of hepatocyte polarity is essential for many functions of hepatocytes and requires carefully orchestrated cooperation between cell adhesion molecules, cell junctions, cytoskeleton, extracellular matrix and intracellular trafficking machinery. The process of hepatocyte polarization requires energy and, if abnormal, may result in severe liver disease. A number of inherited disorders affecting tight junction and intracellular trafficking proteins have been described and demonstrate clinical and pathophysiological features overlapping those of the genetic cholestatic liver diseases caused by defects in canalicular ABC transporters. Thus both structural and functional components contribute to the final hepatocyte polarity phenotype. Many acquired liver diseases target factors that determine hepatocyte polarity, such as junctional proteins. Hepatocyte depolarization frequently occurs but is rarely recognized because hematoxylin-eosin staining does not identify the bile canaliculus. However, the molecular mechanisms underlying these defects are not well understood. Here we aim to provide an update on the key factors determining hepatocyte polarity and how it is affected in inherited and acquired diseases. Copyright © 2015. Published by Elsevier B.V.
    Journal of Hepatology 06/2015; 1. DOI:10.1016/j.jhep.2015.06.015 · 10.40 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatitis C virus (HCV) chronic infection is a major cause of hepatocellular carcinoma. Sorafenib is the only medical treatment that has been approved for the treatment of this cancer. It is a multikinase inhibitor with anti-tumor activity against a wide variety of cancers. Sorafenib blocks angiogenesis and tumor cell proliferation through inhibition of kinases, such as VEGFR2, PDGFR, or the serine/threonine kinases RAF. Previous studies have reported an anti-HCV effect of sorafenib in vitro, but various mechanisms of action have been described. The aim of this study was to clarify the action of sorafenib on the complete HCV infectious cycle. In order to examine the action of sorafenib on all steps of the HCV infectious cycle, we used a combination of validated cell culture models, based on the HuH-7 reference cell line and primary human hepatocytes. We found that sorafenib blocks HCV infection by altering the viral entry step and the production of viral particles. Moreover, we observed that treatment with sorafenib lead to a modification of Claudin-1 expression and localization, which could partly be responsible for the anti-HCV effect. Collectively, our findings confirm the anti-HCV effect of sorafenib in vitro, while highlighting the complexity of the action of sorafenib on the HCV infectious cycle. Copyright © 2015. Published by Elsevier B.V.
    Antiviral research 03/2015; 24. DOI:10.1016/j.antiviral.2015.03.012 · 3.94 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Uptake of hepatitis C virus (HCV) into hepatocytes is an orchestrated process, involving numerous host factors, virion-associated lipoproteins, and a growing number of cell-associated factors. Several of these factors likely contribute to the hepatotropism and limited host range of this virus. Discerning the minimal set of human-specific factors required for viral uptake into nonhuman cells has facilitated the development of small animal models with inheritable HCV susceptibility. This review summarizes current knowledge of host factors required for HCV entry, the molecular mechanisms underlying HCV entry into hepatocytes, and aspects of viral entry contributing to HCV host tropism. Copyright © 2014 Elsevier Inc. All rights reserved.
    Cell Host & Microbe 11/2014; 16(5):562-568. DOI:10.1016/j.chom.2014.10.009 · 12.19 Impact Factor
Show more