Another important finding from these studies is that expression of a subset of these genes in liver biopsies inversely correlated with the responsiveness to IFN-ribavirin therapy, i.e. higher expression was observed in nonresponders as compared to responders. Although this finding is counterintuitive, as one would expect an active IFN system would help eliminate the virus during therapy, it is supported by a number of studies, which have shown that patients with a high ISG expression prior to the initiation of IFN therapy seem to respond poorly to IFN therapy. Additional support is lent from a study showing that the expression of intrahepatic ISGs was already maximally induced in chimpanzees chronically Ruxolitinib infected with HCV. Consequently, when exogenous IFN was administered, there was no further ISG upregulation. Although the underlying mechanism remains elusive, nonresponder hepatitis C patients tend to have pre-activated JakSTAT pathway prior to therapy, which may connect to IFN refractoriness. However, it is important to note that in our study only a subset of the IFN-regulated genes examined were expressed at a statistically significant higher level in patients that were nonresponsive to IFN therapy. Of particular interest, some of these overexpressed genes were either involved in viral sensing or effector functions of IFNs. Both TLR3 and RIG-I can sense HCV RNA early after infection and initiate signaling pathways culminating in the induction of an IFN response that curtails HCV replication. However, HCV has evolved to disarm both mechanisms by NS3/4A-mediated cleavage of the essential adaptor proteins, TRIF, and MAVS, once the infection is established in hepatocytes. Among the ISG effectors, ISG20 and RSAD2 have been shown to inhibit HCV replication, while controversial results have been reported for PKR. There are several possibilities that may explain why induction of the endogenous anti-viral ISGs prior to IFN therapy fails to contain HCV infection. The anti-HCV ISGs may only be transcriptionally upregulated in uninfected surrounding cells but not in HCV-infected hepatocytes. Alternatively, ISG transcripts may be made in both infected and uninfected cells but ISG proteins are only made in uninfected cells because of PKR activation in infected cells. Third, some HCV proteins may inhibit the effector functions of the antiviral ISGs. Regardless of the infection/treatment outcome, underscores the important roles these genes/pathways may play in host attempts to control HCV infection with chronic hepatitis C.