Studies on a role of TGF-beta mimetic activity of HCV NS3 protease in pathogenesis of liver cirrhosis

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Viruses sometimes mimic host proteins and hijack the host cell machinery. Hepatitis C virus (HCV) causes liver fibrosis, a process largely mediated by the overexpression of TGF-beta and collagen, although the precise underlying mechanism is unknown. We found that HCV non-structuralprotein 3 (NS3) protease affects the antigenicity and bioactivity of TGF-beta2 in (CAGA)9-Luc CCL64 cells and in human hepatic cell lines via binding to TGF-beta type I receptor (TbetaRI). TNF-alpha facilitates this mechanism by increasing the colocalization of TbetaRI with NS3 protease on the surface of HCV-infected cells. An anti-NS3 antibody against computationally predicted binding sites for TbetaRI blocked the TGF-beta mimetic activities of NS3 in vitro and attenuated liver fibrosis in HCV-infected chimeric mice. These data suggest that HCV NS3 protease mimics TGF-beta2 and functions, at least in part, via directly binding to and activating TbetaRI, thereby enhancing liver fibrosis.