Chronic hepatitis C viral infection affects approximately 3% of world's population. Despite the progress made over the past decade in understanding the virus, the limited responsiveness of HCV to therapy and the lack of an effective vaccine remain as major scientific challenges. Fundamental to the pathogenesis of HCV is the interaction between the immune system and the virus. T cells appear to play a central role in viral persistence and clearance. However, the mechanisms of how T cells respond to HCV infection and how the virus exerts influence on T cells are not understood. This seriously hampers the development of strategies for immunotherapy and vaccine. One major obstacle in HCV immunopathogenesis research is the lack of adequate and robust cell culture systems and small animal models. The goal of our research is to establish a reliable in vitro and in vivo murine model for studying HCV immune response. To achieve this end, we have successfully established several HCV replicon cell lines from immortalized mouse hepatocyte cell lines, and have developed a methodology to repopulate mouse liver with the mouse HCV replicon cell lines. In this application, we will test the feasibility of this mouse model to study the host immune response to HCV. The objective will be achieved in the following specific aims: First, we will utilize the in vitro cell culture system to investigate the interactions between murine HCV-specific CD8+ T cells and the target murine hepatocytes that support HCV RNA replication; Second, we will develop an in vivo murine model by repopulating HCV replicon-containing hepatocytes in mouse liver, to investigate the effect of the host immune response on HCV RNA replication and liver pathology. Once this mouse model system is proven to be feasible and reliable by the proposed experiments, we will further characterize the interactions between immune competent cells and target hepatocytes. The knowledge derived from these studies may contribute significantly to the development of effective immunotherapies and vaccines.
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