Conclusions: These results demonstrate a role for Pol in HBV-mediated antagonization of IFN-α signaling and provide a possible molecular mechanism

by which HBV resists the IFN therapy and maintains its persistence. (HEPATOLOGY 2013;) Chronic hepatitis B (CHB) caused by hepatitis B virus (HBV) is a serious health problem worldwide. The mechanism by which chronic infection is established and maintained is unknown but is thought to be due, in part, to a suppressed host immune response. One key component RGFP966 manufacturer of the host antiviral responses is the interferon (IFN) system. Viral infection of the host initiates Sunitinib nmr the synthesis of

type I IFNs, which consist predominantly of IFN-α and IFN-β (IFN-α/β). By binding to type I IFN receptors, IFN-α/β triggers the oligomerization and tyrosine phosphorylation of the two tyrosine kinases of the Janus family, Janus kinase 1 and tyrosine kinase 2, which in turn phosphorylate a single tyrosine residue of signal transducer and activator of transcription (STAT) 1 and 2. The activated STAT1/2 heterodimerize with interferon regulatory factor 9 (IRF9) to form the ISGF3 transcription factor complexes and then translocate into the nucleus, where they bind to the interferon-stimulated response element (ISRE) in the promoter of interferon-stimulated genes (ISGs) to initiate transcription of ISGs.1 IFN-α has been shown to inhibit HBV replication in a variety of systems. However, about 70% of CHB patients respond poorly to exogenous IFN-α treatment.2, 3 Increasing evidence suggests that HBV has developed strategies to counteract the type I IFN system, which may contribute to the ineffectiveness of IFN-α therapy.4, 5 We have shown that HBV polymerase (Pol) is able to inhibit IFN-α–induced MyD88 Adenylyl cyclase induction

and nuclear translocation of STAT1.6 Consistently, it could be demonstrated in a chimeric mice model that HBV infection reduced IFN-α–mediated ISG production and STAT1 translocation.7 However, it is still unknown whether the translocation of STAT1 is impaired in chronic hepatitis B patients as well, and the molecular mechanism by which Pol interferes with the IFN responses remains unclear. In this study, we used cell and mouse models to gain a detailed understanding of how HBV and Pol interferes with IFN-α–induced STAT activation. Furthermore, liver biopsies of CHB patients were used to obtain more information on the blockage of IFN-α–induced STAT nuclear translocation by HBV.