Furthermore, sustained expression of ISG15 has been shown to stabilize USP18 and negatively regulate IFN signaling, which facilitates pro-viral responses that are associated with chronic viral hepatitis [88,89], whereas depletion of USP18 has been demonstrated to potentiate anti-HCV activity of IFN by more than 40 fold [90], suggesting that at least in liver, upregulation of USP18 blunts type I IFN signaling and subsequently leads to an increase in HCV production. Here, USP18 is linked to animal viral hepatitis.