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␥), tumor necrosis factor alpha (TNF␣), and IFN␣/␤. In the present study, we crossed HBV transgenic mice with mice genetically deficient for IFN␥ (IFN␥KO), the TNF␣ receptor (TNF␣RKO), or the IFN␣/␤ receptor (IFN␣/␤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␥KO and IFN␣/␤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␥ mediates most of the antiviral effect of the CTLs while IFN␣/␤ 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␣/␤ observed after injection of poly(I ⅐ C) is sufficient to inhibit HBV replication and that a similar antiviral effect is achieved by systemic administration of very high doses of IFN␣. We also compared the relative sensitivity of LCMV and adenovirus to control by IFN␥, TNF␣, or IFN␣/␤ in these animals. Importantly, IFN␣/␤RKO mice, and to a lesser extent IFN␥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.Hepatitis B virus (HBV) is a noncytopathic, enveloped virus that causes acute and chronic hepatitis and hepatocellular carcinoma (4). We have previously shown that the intrahepatic induction of gamma interferon (IFN␥), tumor necrosis factor alpha (TNF␣), and IFN␣/␤ downregulates HBV replication noncytopathically in the livers of transgenic mice (8, 9). This antiviral effect can be achieved by injecting transgenic mice with HBV-specific cytotoxic T lymphocytes (CTLs) (10) or infecting them with an unrelated hepatotropic virus, such as lymphocytic choriomeningitis virus (LCMV) or adenovirus (3, 7).The CTL-dependent effect occurs within 24 h and appears to be mediated by both IFN␥ and TNF␣, since it is possible to block the regulatory effects of the CTLs by the prior administration of a cocktail of antibodies to these cytokines (10). Whether the antiviral cytokines are produced by the passively transferred CTLs or by host-derived cells is unknown.The LCMV-and adenovirus-dependent effect occurs in two distinct phases. The first phase occurs within 12 to 24 h and is mediated by IFN␣/␤ and/or TNF␣ induced by the infecting virus, since it is blocked by a cocktail of antibodies to these cytokines (3). The second phase occurs 5 to 7 days after infection and is associated with the intrahepatic i...

We have previously shown that interferon and tumor necrosis factor noncytopathically abolish hepatitis B virus (HBV) replication from the hepatocyte and kidney tubular epithelial cells in vivo. Here we show that a persistent lymphocytic choriomeningitis virus (LCMV) infection is cleared from the hepatocyte noncytopathically when the same cytokines are induced in the liver by antigen-nonspecific stimuli. These results indicate that, like HBV, LCMV is also susceptible to intracellular inactivation by cytokine-induced antiviral mechanisms that are operative in the hepatocyte. In contrast, LCMV is not cleared from intrahepatic nonparenchymal cells or splenocytes, indicating that, unlike the hepatocyte, these cells do not produce the factors required to inactivate LCMV. Antiviral mechanisms like these may have evolved to maintain the functional integrity of vital organs in the face of massive infection.

We have previously identified two antiviral cytokines (interferon [IFN]-γ and IFN-α/β) that downregulate hepatitis B virus (HBV) replication in the liver of transgenic mice. The cytokine-inducible downstream events that inhibit HBV replication have not been identified. One possible factor is nitric oxide (NO), a pleiotropic free radical with antiviral activity that is produced in the liver by the inducible NO synthase (iNOS). To examine the role of NO in our model, we crossed transgenic mice that replicate HBV with mice that lack a functional iNOS. Importantly, iNOS-deficient mice were almost completely resistant to the noncytopathic inhibitory effect of HBV-specific cytotoxic T lymphocytes on viral replication, an effect that we have shown previously to depend on the intrahepatic induction of IFN-γ. Conversely, iNOS-deficient mice were not resistant to the antiviral effect of IFN-α/β induced by either polyinosinic-polycytidylic acid complex or by lymphocytic choriomeningitis virus (LCMV) infection. These results indicate that NO mediates the antiviral activity of IFN-γ, whereas the antiviral activity of IFN-α/β is NO independent. We also compared the relative sensitivity of LCMV to control by NO in these animals. Interestingly, LCMV replicated to higher levels in the liver of iNOS-deficient mice than control mice, indicating that NO controls LCMV replication in the liver, as well as HBV.

Although coinfection of hepatitis B virus (HBV) and Schistosoma mansoni is a frequent event in humans, little is known about the interactions between these two pathogens. S. mansoni infection induces T helper cell type 2 (Th2)–type cytokines in the liver of humans and mice. The intrahepatic induction of nitric oxide (NO) and Th1-type cytokines, such as interferon (IFN)-γ and IFN-α/β, inhibits HBV replication noncytopathically in the liver of transgenic mice. To examine whether S. mansoni infection and the accompanying induction of Th2-type cytokines could interfere with HBV replication in the liver, HBV transgenic mice were infected with S. mansoni. By 5 wk after infection, HBV replication disappeared concomitant with the intrahepatic induction of NO and Th1-type cytokines, and in the absence of Th2-type cytokines. By 6–8 wk after infection, HBV replication remained undetectable and this was associated with further induction of NO and Th1-type cytokines together with the appearance of Th2-type cytokines. The S. mansoni–dependent antiviral effect was partially blocked by genetically deleting IFN-γ, although it was unaffected by deletion of IFN-α/β. These results indicate that IFN-γ (probably via NO) mediates most of this antiviral activity and that Th2-type cytokines do not counteract the antiviral effect of IFN-γ. Similar events may suppress HBV replication during human S. mansoni infection.