MOLECULAR AND COMPUTER ANALYSIS OF THE HEPATITIS B VIRUS GENOME

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Hepatitis B virus (HBV) is the prototype member of the hepadnavirus family, which consists of hepatotropic viruses that infect at least six separate species. Infection with HBV causes polymorphic liver diseases including acute or fulminant hepatitis, chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Over 300 million people throughout the world are chronically infected with HBV and are at risk of developing hepatocellular carcinoma, one of the world's most prevalent forms of cancer. Recently, two classes of HBV mutants have been identified. The first is an antigenic variant of the virus surface (S) gene that was found in individuals who had received immunoprophylaxis for hepatitis B. In each case an identical single nucleotide substitution occurred that resulted in a single amino acid change in a loop of the S protein known to be important in neutralization of the virus and in stimulation of protective immunity. The emergence of this S-gene mutant form of HBV raises important questions about the significance of such neutralization escape mutants and the possible effect they may have on the efficacy of existing monoclonal (recombinant) vaccines for hepatitis B. The second HBV variant discovered recently has a single nucleotide substitution int he precore gene that results in the premature termination of this protein. This variant is associated with fulminant hepatitis in several regions of the world. The objectives of this study are to: (1) establish an animal model for the study of S- and precore gene mutants, (2) establish and determine the infectivity titer of a challenge pool of S-gene mutant virus, (3) determine the ability of licensed recombinant hepatitis B vaccines to protect chimpanzees against challenge with the S-gene mutant, (4) modify existing vaccines, if necessary, to increase their protective efficacy against S- gene mutants, and, (5) determine the complete nucleotide sequence of the precore variant.