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The Tight Junction Proteins Claudin-1, -6, and -9 Are Entry Cofactors for Hepatitis C Virus

Laurent Meertens,¹ Claire Bertaux,¹ Lisa Cukierman,¹ Emmanuel Cormier,^1, Dimitri Lavillette,² François-Loïc Cosset,² and Tatjana Dragic^1*

Albert Einstein College of Medicine, Department of Microbiology and Immunology, 1300 Morris Park Avenue, Bronx, New York 10461,¹ FR128, Inserm, U758, Ecole Normale Supérieure, 46 Allée d'Italie, 69364 Lyon Cedex 07, France²

Received 8 September 2007/ Accepted 14 January 2008

Hepatitis C virus (HCV) is a major cause of liver disease in humans. The CD81 tetraspanin is necessary but not sufficient for HCV penetration into hepatocytes, and it was recently reported that the tight junction protein claudin-1 is a critical HCV entry cofactor. Here, we confirm the role of claudin-1 in HCV entry. In addition, we show that claudin-6 and claudin-9 expressed in CD81⁺ cells also enable the entry of HCV pseudoparticles derived from six of the major genotypes. Whereas claudin-1, -6, and -9 function equally well as entry cofactors in endothelial cells, claudin-1 is more efficient in hepatoma cells. This suggests that additional cellular factors modulate the ability of claudins to function as HCV entry cofactors. Our work has generated novel and essential means to investigate the mechanism of HCV penetration into hepatocytes and the role of the claudin protein family in HCV dissemination, replication, and pathogenesis.

Published ahead of print on 30 January 2008.

Present address: International AIDS Vaccine Initiative, 369 Fulham Road, London SW10 9NH, United Kingdom.