Claudin 1 as a target for anti-hepatitis C virus strategy

Abstract

Chronic hepatitis C virus (HCV) infection is a global public health issue because ～30% of HCV-carriers develop severe liver diseases including hepatic steatosis, cirrhosis, and hepatocellular carcinoma. Not only viral factors but also host/viral interactions are promising targets for antiviral preventive and therapeutic strategies. Recent studies showed that a tight junction protein claudin 1 is involved in HCV entry into host cells. Consistent with these studies, we isolated the several hepatic Huh7-derived cell clones defective in claudin 1 as HCV-resistant mutants, and cellular permissiveness to HCV was restored by expression of claudin 1 into these cell mutants. These results strongly suggest that claudin 1 is a promising target for antiviral therapy. We thus tried to isolate antibodies against extracellular domain of human claudin 1. Finally we established four mouse anti-claudin 1 monoclonal antibodies by using DNA immunization method and hybridoma screening with the above claudin 1-defective mutant. In the cell culture-infection system using Huh7.5.1 cells and HCV-JFH1 strain, these four antibodies efficiently inhibited infection by HCV in a dose-dependent manner, but do not affect tight junction localization of claudin 1 and cellular barrier function. These monoclonal antibodies targeting claudin 1 might be useful for preventing HCV infection, such as after liver transplantation, and also blocking viral spread in HCV-infected patients.