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J. Virol. doi:10.1128/JVI.02286-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

CD81 and Claudin 1 co-receptor association: a role in hepatitis C virus entry

Division of Immunity & Infection, Institute for Biomedical Research, Division of Immunity and Infection, University of Birmingham, UK; Liver Laboratories, Institute for Biomedical Research, University of Birmingham and University Hospital Birmingham NHS Foundation Trust, UK; Department of Cell Biology and Genetics, Life Science College, Peking University, Beijing, China; Department of Pathology, University of Birmingham and University Hospital Birmingham NHS Foundation Trust, UK; Novartis Vaccines and Diagnostics, Inc., Emeryville, California, USA

	Abstract

Hepatitis C virus (HCV) is an enveloped positive-stranded RNA hepatotropic virus. HCV pseudoparticles infect liver derived cells, supporting a model where liver specific molecules define HCV internalization. Three host cell molecules have been reported to be important entry factors or receptors for HCV internalization: scavenger receptor BI (SR-BI), the tetraspanin CD81 and the tight junction protein Claudin-1 (CLDN1). None of the receptors are uniquely expressed within the liver leading us to hypothesize that their organization within hepatocytes may explain receptor activity. Since CD81 and CLDN1 act as co-receptors during late stages in the entry process, we investigated their association in a variety of cell lines and human liver tissue. Imaging techniques have been developed that take advantage of fluorescence resonance energy transfer (FRET) to study protein-protein interactions. AcGFP and DsRed tagged forms of CD81 and CLDN1 co-localize and FRET occurred between the tagged co-receptors at comparable frequencies in permissive and non-permissive cells, consistent with the formation of co-receptor complexes. FRET occurred between antibodies specific for CD81 and CLDN1 bound to human liver tissue, suggesting the presence of co-receptor complexes in liver tissue. HCV infection and treatment of Huh-7.5 cells with recombinant HCV E1E2 glycoproteins and anti-CD81 monoclonal antibody modulated homotypic (CD81-CD81) and heterotypic (CD81-CLDN1) co-receptor protein association(s) at specific cellular locations, suggesting distinct roles in the viral entry process.

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