Chronic infection with human hepatitis B virus (HBV) leads to liver damage, cirrhosis and liver cancer. The applicant's goal is to elucidate the molecular basis of pathogenicity, chronicity, and clearance of HBV infection. Although chronicity has been attributed to host factors, such as the immune response, viral factors per se have remained largely uninvestigated. The applicant's preliminary results suggest that in chronic carriers and hepatoma patients HBV-acquired mutations may cause antigenic changes that lead to escape from the immune system. They propose to test more directly and definitively the hypothesis that accumulation of certain viral mutations is crucial for the persistence of pathogenic HBV during its long term interaction with the host. The immunopathological interactions between certain HBV core antigen mutants and the host will be studied via assays for peptide-major histocompatibility complex (peptide-MHC) binding, antigen processing and T cell receptor recognition. Specifically, three aims are proposed:
Aim 1) to test the hypothesis that certain core antigen mutations affect MHC-peptide binding;
Aim 2) to test the hypothesis that aberrant HBV core antigen processing could result from immune escape mutants;
Aim 3) to test the hypothesis that certain core antigen mutations affect TCR peptide-MHC recognition. This last aim may be expanded to include the examination of TCR-antagonistic or agonistic mutant core antigens.
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