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: 41.46). 05/2007; 446(7137):801-5. DOI: 10.1038/nature05654
Source: PubMed


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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    • "Such an overlapping approach increases the chances to identify physiologically important genes and pathways. Using these approaches, HCV was shown to induce the integrin-linked kinase (ILK) signalling cascade (which could trigger actin rearrangement), as well as tight junction signalling pathways (Woodhouse et al., 2010), consistent with the known roles of tight junction proteins in HCV entry and spread (Evans et al., 2007; Ploss et al., 2009). Furthermore , HCV infection disrupts glycolysis, gluconeogenesis and lipid metabolism (Woodhouse et al., 2010). "
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    ABSTRACT: Hepatitis C virus (HCV) remains a major global health burden, with more than 130 million individuals chronically infected and at risk for the development of hepatocellular carcinoma (HCC). The recent clinical licensing of direct-acting antivirals enables viral cure. However, limited access to therapy and treatment failure in patient subgroups warrants a continuing effort to develop complementary antiviral strategies. Furthermore, once fibrosis is established, curing HCV infection does not eliminate the risk for HCC. High-throughput approaches and screens have enabled the investigation of virus-host interactions on a genome-wide scale. Gain- and loss-of-function screens have identified essential host-dependency factors in the HCV viral life cycle, such as host cell entry factors or regulatory factors for viral replication and assembly. Network analyses of systems-scale data sets provided a comprehensive view of the cellular state following HCV infection, thus improving our understanding of the virus-induced responses of the target cell. Interactome, metabolomics and gene expression studies identified dysregulated cellular processes potentially contributing to HCV pathogenesis and HCC. Drug screens using chemical libraries led to the discovery of novel antivirals. Here, we review the contribution of high-throughput approaches for the investigation of virus-host interactions, viral pathogenesis and drug discovery.
    Virus Research 09/2015; DOI:10.1016/j.virusres.2015.09.013 · 2.32 Impact Factor
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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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    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 · 11.34 Impact Factor
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    • "In fact, the list of HCV receptors includes two lipoprotein receptors: the scavenger receptor class B, type I (SR-BI)(Scarselli et al., 2002a) and the low-density lipoprotein receptor (LDLR)(Agnello et al., 1999). The model of HCV entry has become increasingly complicated with six novel entry factors identified over the last eight years only: the tight junction molecules claudin-1 (CLDN1) (Evans et al., 2007) and occludin (OCLN) (Ploss et al., 2009), the epidermal growth factor receptor (EGFR) and the ephrin type-A receptor 2 (EphA2) (Lupberger et al., 2011), the cholesterol uptake molecule Niemann–Pick C1-like 1 (NPC1L1) (Sainz et al., 2012) and the transferrin receptor 1 (TFR1) (Martin and Uprichard, 2013). So far, direct proof of interaction with the virus exists for CD81 and SR-BI only, which were identified as candidate receptors precisely for their ability to bind the HCV envelope glycoprotein, E2 (Pileri et al., 1998; Scarselli et al., 2002a). "
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    ABSTRACT: Hepatitis C virus (HCV) represents a global health concern affecting over 185 million people worldwide. Chronic HCV infection causes liver fibrosis and cirrhosis and is the leading indication for liver transplantation. Recent advances in the field of direct-acting antiviral drugs (DAAs) promise a cure for HCV in over 90% of cases that will get access to these expensive treatments. Nevertheless, the lack of a protective vaccine and likely emergence of drug-resistant viral variants call for further studies of HCV biology. With chimpanzees being for a long time the only non-human in vivo model of HCV infection, strong efforts were put into establishing in vitro experimental systems. The initial models only enabled to study specific aspects of the HCV life cycle, such as viral replication with the subgenomic replicon and entry using HCV pseudotyped particles (HCVpp). Subsequent development of protocols to grow infectious HCV particles in cell-culture (HCVcc) ignited investigations on the full cycle of HCV infection and the virus-host interactions required for virus propagation. More recently, small animal models permissive to HCV were generated that allowed in vivo testing of novel antiviral therapies as well as vaccine candidates. This review provides an overview of the currently available in vitro and in vivo experimental systems to study HCV biology. Particular emphasis is given to how these model systems furthered our understanding of virus-host interactions, viral pathogenesis and immunological responses to HCV infection, as well as drug and vaccine development. Copyright © 2015 Elsevier Inc. All rights reserved.
    Virology 04/2015; 479-480. DOI:10.1016/j.virol.2015.03.014 · 3.32 Impact Factor
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