Hepatitis C virus (HCV) often causes a prolonged and persistent infection, and an association between hepatocellular carcinoma (HCC) and HCV infection has been noted. Understanding the molecular basis of viral pathogenesis is a major challenge in the effort to gain insight into HCV associated disease progression. The pathogenesis of liver damage is likely to be related to both viral and immune mediated factors. HCV core protein displays numerous physicochemical and biological activities. The core protein exhibits in vitro RNA and ribosome binding activities, nucleocytoplasmic localization, a regulatory role on cellular and unrelated viral promoters, and interacts with heterogeneous nuclear ribonucleoprotein K and the cytoplasmic tail of the lymphotoxin-beta receptor. Furthermore, the core protein inhibits programmed cell death (apoptosis) under certain conditions, has a transforming potential on primary rodent cells, and induces hepatocellular carcinoma in transgenic mice. These interesting properties suggest the hypothesis that the core protein may play a critical role in cell growth deregulation, and thus contribute to virus mediated pathogenesis during persistent infection. This pilot research proposal is designed to (1) determine the role of HCV core gene expression in normal human hepatocyte growth and (2) map the core protein domain responsible for human hepatocyte growth regulation. The results from this pilot study will be extremely informative in the characterization of the functional role of HCV core protein in its natural host. The capacity to transform primary human hepatocytes will provide a model to examine in detail the core gene and associated cofactors as they relate to multistage hepatocarcinogenicevents in vitro. The long term goal of this study is to understand the molecular mechanism of HCV core protein mediated pathogenesis and to design effective strategies for intervention of HCV related disease in humans.
