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Inhibition of hepatitis C virus infection by anti-claudin-1 antibodies is mediated by neutralization of E2-CD81-claudin-1 associations.

Krieger, Sophie E and Zeisel, Mirjam B and Davis, Christopher and Thumann, Christine and Harris, Helen J and Schnober, Eva K and Mee, Christopher and Soulier, Eric and Royer, Cathy and Lambotin, Mélanie and Grunert, Fritz and Dao Thi, Viet Loan and Dreux, Marlène and Cosset, François-Loïc and McKeating, Jane A and Schuster, Catherine and Baumert, Thomas F (2010) Inhibition of hepatitis C virus infection by anti-claudin-1 antibodies is mediated by neutralization of E2-CD81-claudin-1 associations. Hepatology (Baltimore, Md.), 51 (4). pp. 1144-57. ISSN 1527-3350

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Identification Number/DOI: 10.1002/hep.23445

The tight junction protein claudin-1 (CLDN1) has been shown to be essential for hepatitis C virus (HCV) entry-the first step of viral infection. Due to the lack of neutralizing anti-CLDN1 antibodies, the role of CLDN1 in the viral entry process is poorly understood. In this study, we produced antibodies directed against the human CLDN1 extracellular loops by genetic immunization and used these antibodies to investigate the mechanistic role of CLDN1 for HCV entry in an infectious HCV cell culture system and human hepatocytes. Antibodies specific for cell surface-expressed CLDN1 specifically inhibit HCV infection in a dose-dependent manner. Antibodies specific for CLDN1, scavenger receptor B1, and CD81 show an additive neutralizing capacity compared with either agent used alone. Kinetic studies with anti-CLDN1 and anti-CD81 antibodies demonstrate that HCV interactions with both entry factors occur at a similar time in the internalization process. Anti-CLDN1 antibodies inhibit the binding of envelope glycoprotein E2 to HCV permissive cell lines in the absence of detectable CLDN1-E2 interaction. Using fluorescent-labeled entry factors and fluorescence resonance energy transfer methodology, we demonstrate that anti-CLDN1 antibodies inhibit CD81-CLDN1 association. In contrast, CLDN1-CLDN1 and CD81-CD81 associations were not modulated. Taken together, our results demonstrate that antibodies targeting CLDN1 neutralize HCV infectivity by reducing E2 association with the cell surface and disrupting CD81-CLDN1 interactions. Conclusion: These results further define the function of CLDN1 in the HCV entry process and highlight new antiviral strategies targeting E2-CD81-CLDN1 interactions.

Type of Work:Article
Date:2010 (Publication)
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:Immunity and Infection
Subjects:R Medicine (General)
QR355 Virology
QR180 Immunology
QR Microbiology
Institution:University of Birmingham
Copyright Holders:the American Association for the Study of Liver Diseases
ID Code:464
Refereed:YES
Local Holdings:
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