The hepatitis B virus (HBV) is a small, enveloped hepatotropic virus with a double stranded DNA genome that causes acute and chronic necroinflammatory liver disease (hepatitis) and hepatocellular carcinoma. Since HBV is not directly cytopathic for the infected hepatocyte, the cellular immune response to HBV encoded antigens is thought to be responsible for the liver disease caused by HBV, and to play an important role in viral clearance as well. Because HLA class I restricted, CD8- positive cytotoxic T lymphocytes (CTL) are known to interact directly with processed viral peptides at the cell surface, we have proposed that they play a direct role in viral clearance by destroying infected cells, and possibly by non-cytolytic anti-viral mechanisms as well. During the past several years we established the necessary models and technology to test this hypothesis. In a recent series of studies, we demonstrated that patients with acute viral hepatitis who eventually clear the virus develop a polyclonal, HLA class I restricted, CD-8 positive CTL response to multiple HBV encoded antigens, but that this response is not detectable in patients with chronic HBV infection. We now propose to define the molecular and cellular characteristics of the HBV specific CTL response during acute and chronic viral hepatitis, and to determine the role it plays in viral clearance and liver cell injury. A desired by- produce of this research may be the rational design of CTL-based therapeutic strategies to terminate persistent HBV infection, thereby reducing the human and economic toll of chronic liver disease and hepatocellular carcinoma in the 300 million chronic HBV carriers alive throughout the world today. Because of the power of the technology we have developed, the same strategy can be applied to study the CTL response to any human pathogen whose genome has been cloned and sequenced.
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