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 liver4, 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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The authors thank J. Tassello, M. Hunter and N. Torres for excellent technical assistance; S. You for providing HCVcc/Rluc virus stocks; D. Schmid and M. Landthaler for expert advice on RNAi; and M. MacDonald and L. Dustin for reviewing the manuscript. This work was supported by the Greenberg Medical Research Institute, the Ellison Medical Foundation, the Starr Foundation, the Ronald A. Shellow Memorial Fund, the Richard Salomon Family Foundation, and the National Institutes of Health (grants to M.J.E., T.v.H., D.M.T., A.J.S., P.D.B. and C.M.R.). P.D.B. is an Elizabeth Glaser Pediatric AIDS Foundation Scientist. C.M.R. is an Ellison Medical Foundation Senior Scholar in Global Infectious Diseases. T.v.H. and B.W. were supported by postdoctoral fellowships from the Deutsche Forschungsgemeinschaft. This work was presented in part at the 13th International Meeting on Hepatitis C Virus & Related Viruses, Cairns, Australia, 27–31 August, 2006.
Author Contributions M.E., T.v.H. and C.M.R. designed the project, analysed results and wrote the manuscript. M.E., T.v.H., D.M.T., A.J.S., M.P. and B.W. performed the experimental work. T.H. and P.D.B developed the screening technology and assisted in its implementation. T.v.H. and J.A.M were involved in preliminary experiments identifying and characterizing HCV nonpermissive cell lines.
This file contains Supplementary Methods and Notes with a more in-depth description of the methods and materials employed in this study, additional references and Supplementary Figures 1-8 with Legends. The Supplementary Figures provide additional information on the screening approach that led to the identification of CLDN1 as an HCV co-receptor. They also show more data to support its essential role at the post-binding stage of the HCV entry process.