The replicon system can be used not only to test the effect of a given gene on viral replication, but also for the effects on the IFN response. Previous studies have demonstrated that HCV 1b genotype RNA replication is sensitive to IFN-a treatment, even at low doses. In fact, the roles of two of the genes on our list of eighteen, MxA and GIP3/IFI6-16, have already been examined. The IFN inhibition of HCV 1b replicon RNA replication is independent of MxA, and transient transfection of GIP3 does not itself inhibit the 1b replicon but does enhance the effect of IFNa. We will now study the roles of the remaining genes in our list using the HCV genotype 1a replicon. The studies described below outline our approach for the ISG15 and UBP43 genes; however, similar strategies will be employed for the other genes of interest.