Study on molecular mechanisms of hepatitis C virus infection.

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Although several cell surface molecules such as hCD81, LDL-R, SR-B1, and DC-SIGN have been proposed as candidates for hepatitis C virus (HCV) receptor, it is still unclear if any of these molecules can play a role as a functional cellular receptor, due to the lack of robust and reliable in vitro cell culture systems to propagate HCV. As a surrogate system for the study of HCV infection, pseudotype viruses bearing HCV envelope glycoproteins based on vesicular stomatitis viruses (HCVpv) and retroviruses (HCVpp) have been developed. We have previously shown that human fibroblast growth factor receptor (hFGFR) 4 is a binding receptor for HCV based on the specific binding with HCVpv, HCV-like particles and authentic HCV particles in patient sera. Recently we found that HCVpv generated in 293T cells and CHO cells (HCVpv/CHO) exhibit hCD81-dependent and -independent infection, respectively. Infection of HCVpv/CHO to HepG2 cells was inhibited by hFGF2, a soluble protein representing the ectodomain of hFGFR5 fused with the Fe region of IgG (hFGFR5/Fc), or anti-hFGFR5 antibody. Overexpression of hFGFR5 in 293T and Huh7 cells enhanced the susceptibility to HCVpv/CHO infection. In contrast, siRNA-mediated knockdown of hFGFR5 in HepG2 cells resulted in the reduction of infectivity of HCVpv/CHO. Furthermore, binding of the authentic HCV particles in patient sera to HepG2 cells was inhibited by the hFGFR5/Fc. Finally, expression of hFGFR5 (but not hFGFR4) in CHO cells rendered them permissive for HCVpv/CHO infection. Together, these results suggest the possible involvement of hFGFR5 in the internalization process of HCV in a hCD81-independent fashion.