Hepatitis C virus (HCV) infection in humans is almost invariably associated with viral persistence and chronic hepatitis. Chronic hepatitis C is a major risk factor for the development of hepatocellular carcinoma. The high incidence of HCV persistence suggests that this virus has evolved one or more mechanisms to evade and possibly suppress T lymphocyte responsiveness. To understand the mechanism(s) involved in the establishment of HCV persistence, we have identified HCV core protein as an immunomodulatory molecule capable of suppressing host immune response. To investigate a molecular basis of HCV core-mediated immune suppression, we identified a gene encoding the C1q complement receptor, gC1qR as a host target, which binds HCV core protein by the yeast two hybrid in our initial attempt to search for a host protein(s) capable of association with HCV core. Evidence has been obtained that this association is highly specific. C1q is a ligand of gC1qR and is involved in the early defense against infection and regulation of adaptive immunity. Like C1q, HCV core can inhibit the human T lymphocyte proliferative response. These observations lead to a hypothesis that the HCV core/gC1qR-mediated inhibition of T cell function may play a critical role in the establishment of HCV persistent infection. This proposal is to investigate the underlying mechanism for HCV core-mediated suppression of T cell function and analyze a structural basis for HCV core and gC1qR interaction. First, we will elucidate the mechanism involved in the inhibition of T lymphocyte proliferative response by HCV core. Second, we will further define and characterize the molecular interaction between HCV core protein and gC1qR. Lastly, we will characterize the inhibition of T cell function by core proteins from acute and persistent infection. The proposed studies will help to understand the mechanism for the establishment of HCV persistence. In addition, they will provide a basis for the rational design of vaccines and novel therapeutic agents to block the action of HCV core/gC1qR on suppression of T cell function.
