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Extracellular Networks Responsible for the Noncytopathic Inhibition of Expression and Replication of Hepatitis B Virus Genes in Transgenic Mice

L.G. Guidotti

To better understand the complex network of molecular interactions responsible for antiviral effects in mice transgenic for hepatitis B virus (HBV), we crossed HBV transgenic mice with mice genetically deficient in IFN-, the receptor for TNF-, or the receptor for IFN type I to determine whether these cytokines work independently or synergistically. Preliminary results suggest that mice lacking the receptor for IFN type I replicate HBV at higher levels than do mice deficient in IFN- or the receptor for TNF- and are relatively resistant to the cytokine-induced inhibition of HBV replication that occurs after transfer of HBV-specific cytotoxic T lymphocytes (CTLs) or after infection with unrelated hepatotropic viruses.

Kupffer cells are the resident macrophages of the liver. They account for 80--90% of the total macrophages in the body. When activated, they release a large variety of inflammatory cytokines, chemokines, and other products such as nitric oxide, superoxide anion, hydrogen peroxide, and prostaglandins. We think that activation of Kupffer cells may be a key step in the clearance of HBV from the liver, because hepatic expression and replication of HBV genes are permanently and noncytopathically abolished when Kupffer cells are infected with and activated by lymphocytic choriomeningitis virus in the absence of a specific cellular immune response.

We are monitoring the expression and replication of HBV genes and the intrahepatic cytokine, chemokine, and cytokine receptor profiles that occur after activation of Kupffer cells. As expected, macrophage activators such as polyinosinic-polycytidylic acid complex inhibit HBV replication efficiently. Furthermore, to examine the role of nitric oxide in our model, we crossed HBV transgenic mice with knockout mice that lack a functional inducible nitric oxide synthase; experiments in these animals are in progress.

Thus, it appears that local secretion of type I cytokines directly and indirectly (via the release of macrophage-derived antiviral factors) can "cure" HBV infection. If this finding is correct, viral persistence could be due to a quantitative or qualitative deficiency of either the antigen-specific or the antigen-nonspecific cellular immune response. The latter situation might occur if the type 1 immune response wanes or the cytokine profile is redirected toward a type 2 response that has cytopathic activity without suppression of HBV replication.

It is well known that certain parasites, including Leishmania and Schistosoma, induce type 2 responses in the liver of experimentally infected mice. It is also known that patients with chronic HBV infections who are coinfected with Schistosoma have more severe liver disease than do patients with HBV infection only. This finding suggests that an intrahepatic type 2 immune response may not be sufficient to clear HBV, thereby contributing to chronic infection. To test this hypothesis, we are infecting HBV transgenic mice with Schistosoma mansoni and are analyzing HBV replication in these animals.