Understanding Immunopathogenesis of Hepatitis B Virus

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DESCRIPTION (provided by applicant): Hepatitis B Virus (HBV) is a hepadnavirus that is a major cause of acute and chronic hepatitis in humans. Three hundred million people globally are chronically infected with HBV, making HBV one of the most common human pathogens. HBV replication is not cytopathic, and evidence has shown that hepatic pathology is immune-mediated. Thus, understanding the pathogenesis of acute and chronic hepatitis B virus infection mandates understanding the immune responses underlying these processes. Natural hepadnaviral infections occur only in humans and other outbred species whose immune systems are poorly characterized and difficult to study. This proposal seeks to use a new transgenic mouse model of hepatitis B virus infection to identify mechanisms involved in immunopathogenesis of acute and chronic hepatitis B virus infection, including understanding the role of the innate immune response in these disease processes. It is our hope that in identifying mechanisms underlying these disease processes, we will be able to design specific immunotherapies to prevent and treat HBV-related liver disease. Our specific aims are: 1. To determine the mechanism by which non-classical NKT cells mediate acute experimental hepatitis in our transgenic mouse model of primary HBV infection; 2. To test the hypothesis that the early activation of non-classical NKT cells and/or NK Cells in our model of primary HBV infection can significantly influence the chronic phase of hepatitis in our disease model; and 3. To develop an in vitro model of non-classical NKT cell activation in response to Hepatitis B virus, which will establish a fundamental experimental system for identifying the mechanisms of non-classical NKT cell activation.