ISG15 and UBP43/USP18, which are components of a newly-recognized IFN regulatory pathway, are perhaps the most interesting subset of genes that were found to be differentially expressed in our studies. Both genes are expressed more highly in nonresponder (NR) compared with responder (R) liver tissue, suggesting that they might interfere with the immune response in HCV-infected liver ISG15 is a ubiquitin-like (Ubl) protein which is thought to be important to innate immune functions and is covalently linked to proteins following interferon activation. How this link is accomplished is controversial and may involve some overlap with known E2 Ub enzymes. Interestingly, the E2 Ub enzyme UBCH8 was recently identified as an activator of ISG15,34 and is one of the genes upregulated in response to chronic HCV in our microarray analysis. The conjugation of ISG15 to its target proteins is reversed by a highly specific protease, USP18/UBP43. UBP43 belongs to a family of Ub-specific proteases and is induced by IFN, LPS and viral infection; it is degraded by the Skp2 Ub ligase. Loss of USP18 in mice leads to IFN hypersensitivity. Our data links UBP43 with HCV, and suggests that the pathway is important in a divergent host/viral response.