Section I. A possible role for the UBP43, ISG15 Pathway in the HCV Interferon While our gene expression profiles have distinguished two types of chronic HCV infection – one which responds to IFN, and the other that does not - our main objective is to achieve a molecular understanding of the roles of specific genes and proteins in the host response to HCV. Though an altered gene expression level does not directly implicate the gene product in the biological pathway, there are compelling biological reasons to suggest that at least some of the genes on our list play an important role in viral-IFN responses. Several of the most up-regulated genes are interferon-sensitive (including OAS, Mx1, ISG15, VIPERIN, IFIT, and GIP2). Polymorphisms of OAS have been weakly linked to self-limited HCV infection, and polymorphisms of Mx1 have been weakly linked to response status. Hepatic mRNA levels for OAS, Mx1, and GIP2 are increased in chronic HCV but none, alone, have been linked to treatment outcome. The genes that are not directly IFN-responsive may play roles in cellular pathways important for IFN responses (PI3AP1, DUSP1), and are involved in inflammatory cell activation and maturation (LAP).