Relative sensitivity of hepatitis B virus and other hepatotropic viruses to the antiviral effects of cytokines

We have previously shown that hepatitis B virus (HBV) replication is inhibited noncytopathically in the livers of transgenic mice following injection of HBV-specific cytotoxic T lymphocytes (CTLs) or infection with unrelated hepatotropic viruses, including lymphocytic choriomeningitis virus (LCMV) and adenovirus, These effects are mediated by gamma interferon (IFN gamma), tumor necrosis factor alpha (TNF alpha), and IFN alpha/beta. In the present study, we crossed HBV transgenic mice with mice genetically deficient for IFN gamma (IFN gamma KO), the TNF alpha receptor (TNF alpha RKO), or the IFN alpha/beta receptor (IFN alpha/beta RKO) in order to determine the relative contribution of each cytokine to the antiviral effects observed in each of these systems. Interestingly, we showed that HBV replicates in unmanipulated IFN gamma KO and IFN alpha/beta RKO mice at levels higher than those observed in control mice, implying that baseline levels of these cytokines control HBV replication in the absence of inflammation. We also showed that IFN gamma mediates most of the antiviral effect of the CTLs while IFN alpha/beta is primarily responsible for the early inhibitory effect of LCMV and adenovirus on HBV replication. In addition, we showed that the hepatic induction of IFN alpha/beta observed after injection of poly(I . C) is sufficient to inhibit HBV replication and that a similar antiviral effect is achieved by systemic administration of very high doses of IFN alpha, We also compared the relative sensitivity of LCMV and adenovirus to control by IFN gamma, TNF alpha, or IFN alpha/beta in these animals. Importantly, IFN alpha/beta RKO mice, and to a lesser extent IFN gamma KO mice, showed higher hepatic levels of LCMV RNA and adenovirus DNA and RNA than control mice, underscoring the importance of both interferons in controlling these other viral infections as well.