Immune Costimulatory Molecules in HCV Pathogenesis

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DESCRIPTION (provided by applicant): T cell-mediated immune responses have long been proposed to play an important role in the pathogenesis of hepatitis C virus (HCV) infection; however, the molecular basis and potential host targets for novel therapeutics (e.g. siRNA) during this process are not well explored. We hypothesize that the B7 co-stimulatory molecules are required for activation and prolonged survival of HCV specific T cells in the liver and thus key to disease pathogenesis. Two complementary approaches will be used to test this hypothesis in newly developed, liver-specific transgenic mouse models. First, two bigenic transgenic mice that express the structural or full-length HCV proteins and CD86/B7.2 molecules in the liver will be generated. Hepatic HCV-specific and -nonspecific T cells, NK cells and macrophages will be characterized and liver injuries in these animals will be compared with those in single transgenics. To further examine whether HCV-specific T cells can be primed in the liver and whether co-stimulatory signals are necessary for disease initiation and perpetuation, we will next generate conditional bigenic mice that express intrahepatic HCV and CD86/B7.2 molecules upon transgene induction. As HCV-specific T cells are primed intrinsically in these mice, this latter model mimics more closely what occurs in HCV-infected persons. The functions of CD80/B7.1 and CD40 in HCV pathogenesis will also be studied through a hydrodynamic gene delivery technology. Effort will be directed at defining the kinetic production of intrahepatic IFN-( and CC chemokines and its correlation to HCV-directed liver injury. These studies would provide important information on co-stimulatory molecules in HCV pathogenesis and may aid in devising future strategies targeted at blocking specific candidates.