The hepatitis B virus (HBV) causes acute and chronic necroinflammatory liver disease and hepatocellular carcinoma. Over 350 million people worldwide are persistently infected by HBV, representing an enormous reservoir for horizontal and vertical spread of this virus to others. The long term objective of this application is to elucidate the molecular basis for liver disease, viral clearance and viral persistence in the pathogenesis of HBV infection with the ultimate hope that this knowledge will lead to the development of new therapeutic strategies to terminate persistent infection and its attendant costs and complications. Using transgenic mice that replicate HBV at high levels in the liver as recipients of HBV-specific CTLs, we have shown that the antiviral potential of the CTLs is primarily mediated by noricytolytic mechanisms that involve the intrahepatic production of type I inflammatory cytokines by these cells. This occurs after the CTLs specifically recognize viral antigens on the surface of the hepatocyte. Following antigen recognition, the CTLs also trigger the death of a small number of hepatocytes and this process leads to the recruitment of many host-derived lymphomononuclear and polymorphonuclear cells into the liver that contribute to the formation of necroinflaminatory foci histologically identical to classical viral hepatitis in man. The recruited inflammatory cells are likely to be responsible for antigen-nonspecific amplification mechanisms that greatly enhance the liver damage initiated by the CTLs. The recruitment of these cells is probably mediated by secretion of chemokines by either the antigen-activated CTLs or other cellular components of the liver. In support of this, we have performed preliminary experiments showing that a large variety of chemokines are rapidly and strongly induced in the liver of HBV transgenic mice after CTL transfer and their expression is regulated by type 1 inflammatory cytokines. Chemokines are likely to play a role in viral pathogenesis by regulating the trafficking of inflammatory cells to tissue sites of infection and, perhaps, by directly inhibiting viral replication. Whether this is the case during HBV infection is not known. To explore these hypotheses, we will use in vivo (HBV-replicating transgenic mice) and in vitro (HBV-replicating hepatocytes) systems to determine the function of chemokines and chemokine receptors on the recruitment, antiviral and pathogenic effector functions of CTLs and other inflammatory cells. We will also define the role that type 1 inflammatory cytokines may play in these processes. The results of these experiments will provide insight into the basic immunological processes that may determine liver disease, viral clearance and viral persistence in the pathogenesis of HBV infection.