Pathogenesis of Hepatitis B Virus in Transgenic Mice

Scripps Research Institute, The, La Jolla CA

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Abstract

The hepatitis B virus (HBV) is a noncytopathic double-stranded DNA virus that causes acute and chronic tiepatitis, and hepatocellular carcinoma. The long term goal of this application is to elucidate the immunological mechanisms responsible for viral clearance, viral persistence, and disease pathogenesis during HBV infection, and to develop immunotherapeutic strategies to terminate chronic infection. These processes have been difficult to study because of the absence of a cell culture system or a small animal model of HBV infection. We have brought the power of mouse genetics, immunology and cell biology to bear on these important virological questions by developing transgenic, hydrodynamic transfection, and recombinant adenovirus models of HBV in inbred mice. Using those systems, we discovered and defined the dual pathogenetic and noncytopathic antiviral potential of the effector limb of the immune response to HBV, and we have begun to elucidate the cellular and molecular mechanisms responsible for these effects. However, it is also important to understand the early immunological events that occur in response to HBV infection and the mechanisms that regulate the effector functions of that response because they are likely to determine its outcome. Moreover, while failure to mount or sustain a robust immune response against HBV is clearly the proximal cause of chronic infection, the potential therapeutic impact of boosting that response remains to be determined. Our understanding of these events is quite limited because they are extremely difficult to study in humans or other outbred hepadnavirus models. Thus, in Specific Aim 1, we will use our genetically defined HBV-mouse models to probe the dynamics and requirements for induction and maturation of the immune response to HBV when it is expressed de novo in the liver, as occurs during natural HBV infection. In Specific Aim 2, we will study the impact of intrahepatic antigen recognition on the effector functions of the response, since effector suppression is a possible means of viral escape. Finally, in Specific Aim 3, we will attempt to induce an immune response to HBV in immunologically tolerant hosts and, if we succeed, to examine the consequences of that response on the virus and the liver. The information derived from these studies will help us understand why and how some HBV infections resolve while others become persistent. In addition, they could identify new therapeutic options to terminate chronic HBV infection for testing in humans. Their impact on public health could be substantial, since more than 350 million people are chronically infected by HBV and 1million people die each year of this infection.