32 Moreover, Pol and X have been shown to be able to counteract the pattern recognition receptor signaling in hepatocytes.8, 33, 34 Therefore, we speculated that nonparenchymal liver cells may contribute to intrahepatic ISG expression during HBV infection, Selleck PLX-4720 though the mechanisms involved are yet to be determined. In addition, although HBsAg did not influence IFN signaling in vitro, we cannot neglect the role of it and

hepatitis B e antigen in contributing to the IFN response defect in vivo, as they were reported to suppress Toll-like receptor–induced IFN-β and ISG induction in both the parenchymal and nonparenchymal liver cells.35 In addition, the data obtained from liver biopsies revealed that the nuclear translocation of STAT1/2 was impaired in HBV-positive cells, but was still intact in many neighboring cells without HBV infection. Therefore, comprehensive analysis of the interaction between HBV and the IFN system in both hepatocytes and nonparenchymal cells is necessary, PF-562271 concentration and it will be interesting to compare the STAT activation pattern in different types of liver cells between the IFN responders and nonresponders to further explore factors affecting response to IFN-α therapy. Viruses have evolved various strategies to circumvent the IFN response, thus allowing them to escape the host defenses.36 HCV, for example, impairs type I

IFN response by blocking different levels of IFN-α signal pathway via its core, NS3 and NS5A Sorafenib purchase proteins. For HBV, we propose a two-part mechanism by which Pol inhibits the IFN-α–stimulated antiviral responses. These findings, together with our previous finding that Pol can inhibit the type I IFN induction,8 suggest that Pol is a multifunctional IFN antagonist. This knowledge not only helps us understand the mechanisms of resistance of HBV-infected patients to IFN treatment, it also clarifies the role of Pol in HBV persistence. Once viral replication reaches high levels, Pol may exert its anti-IFN activities to ensure the survival

of the virus. Notably, the sensitivity to IFN-α differs between HBV and HCV. It was reported that IFN treatment resulted in a rapid reduction in HCV but a moderate reduction in HBV.37 HBV seems to have a stronger ability to interfere with the IFN antiviral actions compared with HCV. However, the inhibitory effect of HBV on the IFN-α–mediated ISG induction was found to be modest.37 HBV, as a hepatotropic DNA virus, may have low sensitivity to IFN-induced ISGs and counteract the IFN actions at different levels, including the IFN signal transduction and antiviral functions of ISG products. Nevertheless, future studies are required to fully understand HBV resistance to IFN-α and precisely define the mechanisms by which IFN-α inhibits HBV replication.