REGULATION OF HBV REPLICATION BY OTHER HUMAN PATHOGENS

Scripps Research Institute, La Jolla CA

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Abstract

The hepatitis B virus (HBV) causes acute and chronic necroinflammatory liver disease and hepatocellular carcinoma. Over 300 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 understand the host- virus interactions responsible for HBV persistence 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 CTL and hepatotropic viruses such as lymphocytic choriomeningitis virus (LCMV), we have shown that HBV replication is abolished by these agents, noncytopathically, as a result of the intrahepatic induction of interferon alpha, interferon gamma and tumor necrosis factor alpha (type 1 cytokines). We now propose to examine the antiviral regulatory networks that are activated in the LCMV-infected liver in order to identify the ligand-receptor interactions that trigger the hepatocyte to suppress HBV gene expression and replication in vivo. Since the intrahepatic macrophage (Kupffer cell) is an important and well placed source of potentially active antiviral mediators in this system, we will determine whether physiological and pharmacological activation of the Kupffer cell is sufficient to clear HBV from the hepatocyte in vivo. if successful, these studies would establish the concept that inducible cellular crosstalk can control viral infection, perhaps leading to the development of an entirely new area of viral immunotherapeutics. Finally, in view of our findings it is possible that HBV persistence might be favored by inflammatory responses dominated by type 2 cytokines (eg interleukins 4, 5 and 10). To explore this hypothesis, we will determine whether intrahepatic type 2 inflammatory responses initiated by schistosomal and leishmanial infection are able to clear HBV from the liver of these animals. The results of these experiments will not only provide insight into the basic immunological processes that may determine HBV persistence, but additionally they may also shed light on the basis for the more aggressive liver disease that occurs in millions of patients with chronic HBV infection who are superinfected by these parasites in developing countries throughout the world.