siRNA studies: We hypothesize that elimination of UBP43 will lead to less HCV RNA replication at baseline and will magnify the effect of IFN, and that elimination of ISG15 will increase baseline HCV RNA and decrease the effect of IFN. Silencing and control siRNAs will be obtained from Ambion. These will be transfected using GenePorter according to the manufacturer’s instructions; transfection conditions will be optimized using the SV40 promoter/enhancer luciferase control plasmid, pGL2-control, to ensure that increasing amounts of templates results in proportional increases in luciferase activity. Forty-eight hours after the transfection, total RNA or protein samples will be prepared as before. Real-time PCR will be performed to determine mRNA expression in the presence or absence of siRNA, and protein levels will be determined by Western blot. After these control studies have been performed, the effect of siRNA inhibition on baseline and IFN-treated HCV RNA replication will be tested.