IFN-?4 potently blocks IFN-? signalling by ISG15 and USP18 in hepatitis C virus infection.

ABSTRACT: Genetic polymorphisms in IFNL4 have been shown to predict responses to IFN-?-based therapy in hepatitis C virus (HCV)-infected patients. The IFNL4-?G genotype, which encodes functional IFN-?4 protein, is associated with a poor treatment response. In the present study, we investigated the induction and biological effects of IFN-?4 in HCV-infected hepatocytes and their association with responsiveness to IFN-?. We also studied the effects of direct-acting antiviral (DAA) treatment on IFN-?4 expression and IFN-? responsiveness. HCV infection induced IFN-?4 expression at mRNA and protein levels in primary human hepatocytes (PHHs). In hepatoma cells, IFNL4 gene transfection or recombinant IFN-?4 protein treatment robustly increased the protein levels of ISG15 and USP18 in an IFNLR1-dependent manner and potently blocked IFN-? signalling. The ISG15/USP18-mediated IFN-? unresponsiveness was demonstrated by transfection of siRNAs targeting ISG15 and/or USP18. This potent IFN-?4 effect was related to prolonged ISG expression after IFNL4 gene transfection. DAA treatment of HCV-infected PHHs reduced the expression of IFN-?s, including IFN-?4, and restored IFN-? responsiveness. These results demonstrate that virus-induced IFN-?4 potently blocks IFN-? signalling by inducing high protein levels of ISG15 and USP18. Moreover, the data clearly demonstrate that DAA therapy restores IFN-? responsiveness in HCV-infected cells.

SUBMITTER: Sung PS 

PROVIDER: S-EPMC5476576 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature