Pathogenesis of Liver Disease in Hepatitis

Scripps Research Institute, The, La Jolla CA

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Abstract

The hepatitis B virus (HBV) is a noncytopathic, hepatotropic DNA virus that causes acute and chronic hepatitis and kills a million people each year from cirrhosis of the liver and hepatocellular carcinoma. Understanding the mechanisms responsible for viral clearance, persistence and disease pathogenesis during HBV infection is, thus, scientifically and medically important. We have previously shown that the immune response plays a key role in the outcome of HBV infection in humans; and we have used transgenic mice to identify immunological mechanisms that are probably responsible for viral clearance and liver disease. In the current funding interval, we used acutely infected chimpanzees in order to study the early host-virus interactions that occur at the site of infection and likely determine its outcome but, for practical and ethical reasons, aren't accessible in man. Those results indicate that the course and duration of HBV infection are clearly related to the kinetics and extent of viral spread, and to the kinetics, magnitude, quality and cytokine profile of the intrahepatic T cell response. In the next funding interval we will determine which of these factors actually decide the outcome of HBV infection by selectively regulating viral spread, the cellular immune response, inflammatory cytokines, and expression of a putatively immunosuppressive HBV protein in acutely infected chimpanzees. The results of these experiments should establish the basis for viral clearance, persistence and disease pathogenesis in acute and chronic HBV infection, and thereby identify new therapeutic strategies to, hopefully, cure this deadly disease.