During the current funding interval Dr. Chisari established the technology required to detect, quantitative and characterize the cytotoxic T lymphocyte (CTL) response to the hepatitis B and C viruses. Using this technology he defined the salient features of the host-virus relationship during the acute and chronic phases of these infections and, in the process, established the rationale and identified the immunological targets for antigen-specific immunotherapy of chronic hepatitis. Despite these advances, the very early aspects of the host-virus relationship during HBV and HCV infection are completely unexplored because, for practical and ethical reasons, it is extremely difficult to access the incubation period in infected patients. Nonetheless, these early host-virus interactions are likely to be key determinants of the outcome of these infections. In the next funding interval, he will examine the virological, immunological and pathological features of the host-virus relationship from the moment of HBV and HCV infection until their final outcome in experimentally infected chimpanzees. As in humans, almost all adult onset HBV infections in chimps are self limited, while only half of chimp HCV infections are self limited and the rest become persistent. Thus, he will compare and contrast the early intrahepatic T cell responses to HBV and HCV to test the hypothesis that the outcome of these infections is determined by the kinetics, vigor, diversity and cytokine profiles of the intrahepatic T cell response and the ability of the virus to spread and to evade immune recognition during the early incubation period of each infection. Thanks to the close relatedness of chimps and humans, most of the reagents and techniques required to define the intrahepatic antigen specific T cell response to these viruses are already available. The information forthcoming from these studies will, for the first time, define the virological and immunological features of early HBV and HCV infection and determine the extent to which they influence viral clearance and disease pathogenesis in these diseases.
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