Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry

Hepatitis C co-factor Claudin-1, a tight junction protein expressed in human liver, has been identified as an essential entry co-factor for hepatitis C virus. Like the CD81 co-receptor, claudin-1 spans the cell membrane four times with two extracellular loops. It functions in the hepatitis C virus entry process at a post-binding and pre-fusion step. This discovery provides insights into the mechanism of viral entry into liver cells, and a potential new target for antiviral drugs. 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 4 , 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.