About 5 years ago, we began a serious effort to use our experience in molecular virology to ask questions that would help in the design of better protocols for the treatment of chronic hepatitis B virus infections. At the same time, we wished to investigate the connection between chronic infection and liver cancer. We began by studying transient infections, as the paradigm for an ideal antiviral therapy, and determined, to our surprise, that a host can rapidly and completely clear a virus even after weeks or months of infection of the entire hepatocyte population. Moreover, virus clearance was not always associated with a detectable neutralizing antibody response. The early results of this research raised the possibility that infections might be much less stable within hepatocytes or the liver than we had surmised from tissue culture experiments. We therefore initiated a parallel study of the consequences of long-term therapy with a nucleoside analog inhibitor of viral DNA synthesis. Like the analyses of transient infection, this study showed that virus could clear from a substantial portion of the hepatocyte population, even in the absence of any host immune response to the virus. Also, the rate of clearance was apparently governed by the rate of hepatocyte proliferation. These studies and others have set the stage for determining the mechanisms that produce virus-free hepatocytes during transient and chronic infections and how, in the absence of virus clearance, this leads to the selection of neoplastic cells that give rise to liver tumors. The immediate objectives are: 1) To determine how transient-infections are resolved even after infection of the entire hepatocyte population. 2) To determine if the risk of carcinoma in the chronically infected liver can be decreased by agents that terminate an infection or reduce its extent. 3) To define changes in host gene expression that are associated with hepatocellular transformation in the chronically infected liver. These objectives will be pursued using cell culture systems as well as woodchucks infected with woodchuck hepatitis virus and ducks infected with duck hepatitis B virus.
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