Hepatocellular injury in hepatitis B virus (HBV) infection is believed to result from immune-mediated mechanisms related to host clearance of this non-cytopathic virus. Because of this fact and interests in HBV vaccine design, the objective of this proposal is to examine molecular and cellular mechanisms of immune recognition of HBV antigens, and to characterize the antigenic determinants to which the immune response is directed. Specific studies will include: 1) identification of pre-S and nucleocapsid (HBcAg) T and B cell recognition sites as a prerequisite for analysis of the importance of viral subtype in vaccine design, structure-function relationships, T cell tolerance, and cellular interactions; 2) studies of the cellular correlates of the HBV immune response including interaction between Th cell-B cell, Th-CTL, Th-APC; 3) utilization of synthetic peptide antigens to examine mechanisms of HBV-specific T cell tolerance, to explore the concept of T cell immunodominance, and to determine the effects of functional deletion of single T cell populations on antibody production, and CTL function; 4) characterization of HBcAg/HBeAg-expressing inbred transgenic mice in terms of mechanisms of tolerance, which is believed to be responsible for viral persistence in neonates infected with HBV, as well as pathological consequences of an immune response to HBcAg/HBeAg expressed in liver cells, as occurs in acute infection with HBV; and 5) study the potential use of HBcAg as an immunologic carrier moiety for HBV and non-HVB vaccine development. This system has provided and continues to provide, critical information applicable to HBV vaccine design and understanding of pathogenetic mechanisms in HBV infection. As the experimental design expands and the data base increases, it is anticipated that this system will also provide basic information relating to tolerance induction and immune recognition of complex protein antigens.
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