Thus genes such as Mx1 and PKR/EIF2AK2 contain an ISRE, and are induced by the classical IFN-activated signaling that involved JAK1 and TYK2 activation and STAT1 and STAT2 transcription factors. However ISGs such as RIG-I/ DDX58 and MDA5/IFIH1 may be induced through an NF-kBdependent pathway as well. In addition, a number of ISGs such as VISA/MAVS and Casp4 do not contain an ISRE but Oligomycin A rather an SIE and appear to be regulated by STAT1 and STAT3 homodimers and heterodimers. In addition, some SIE-containing ISGs such as IRF1 and MYD88 may also be regulated through an NF-kB-dependent pathway. All 39 members of the IFN-regulated signature gene set were induced upon IFNa treatment of Huh7 hepatoma cells. We found that nearly all 39 of the IFN-response signature genes were expressed in liver biopsies from chronically HCV-infected patients enrolled in the clinical trial of IFN-ribavirin at UTHSC. Previous studies using microarrays to determine global gene expression of liver biopsies from chronically HCV-infected patients and from experimentally HCV-infected chimpanzees show elevated ISG expression. In addition, there was a great deal of heterogeneity in the expression level of the signature genes in the different patients. For example, genes that were expressed at relatively low levels such as IFNb, IL6, TNFRSF10B, VEGFC and ANGPT2 were expressed only in a subset of patient samples. In contrast, genes that were expressed at relatively high levels such as TNFSF10, OAS1, RANTES and IRF9 were detected in all liver biopsies. It is of particular interest that only a small fraction of liver biopsies from patients chronically infected with HCV expressed the IFNb gene. While this seems to conflict with our previous finding that,50% of the serum samples from a smaller patient population in the clinical trial of IFN-ribavirin had detectable levels of type I IFN, it is conceivable that most of the circulating levels of type I IFN derive from extrahepatic sources such as the plasmacytoid dendritic cells. Consistent with our data, two recent studies have shown that type III IFNs rather than type I IFNs are induced in the liver of experimentally HCV-infected chimpanzees and that the intrahepatic level of type III IFNs correlates with that of ISG expression. Our IFN-response geneset did not contain type III IFN genes, since when this study was initiated and the geneset was constructed a role for IL29/IL28B in hepatic innate immunity to HCV infection was not recognized.