We have chosen to explore the role of our genes of interest using the full-length HCV genotype 1a replicon assay, in collaboration with Dr. Charles Rice (Rockefeller University, New York). This replicon is a variant of the full-length HCV H77 strain described recently by Dr. Rice, but has higher levels of replication in cell culture than the previous version. The replicon model is ideal for rapidly testing the effects of many genes and has been used extensively to study HCV mechanisms at a cellular level. This approach will be used for all of the genes identified as of potential interest in the studies above, focusing first on the ISG15 and UBP43 genes, second on the 16 genes remaining in our response-discriminatory list, and finally on novel genes identified in the gene expression studies detailed below.