EPSTI1 Is Involved In IL-28A-mediated Inhibition Of HCV Infection

Hepatitis C virus(HCV) is a single positive-strand RNA virus, which has infected approximately 170 million people worldwide, and causes serious liver diseases such as chronic hepatitis, cirrhosis, and hepatocellular carcinoma.It has been reported that IFN-λs inhibit HCV replication in vitro. But the mechanisms of how IL-28 A conducts antiviral activity and the functions of IL-28A-induced ISGs(IFN-stimulated genes) are not fully understood.In this study, we found that IL-28 A inhibits HCV replication in both HCV full-length replicon cells and viral-infected hepatocytes.And IL-28 A can markedly suppress HCV lifecycle including viral replication, assembly and release but invasion. Treating with IL-28 A or IFN-α can increase ISGs expressions apprevently. But the peak gene expression induced by IFN-α occurs earlier than that induced by IL-28 A, while the induction of ISGs by IL-28 A lasts longer than IFN-α. The combination of IL-28 A and IFN-α synergistically upregulates inhibition of HCV, ISGs expression and STATs phosphorylation level. All of these suggest IL-28 A and IFN-α have synergetic effects. EPSTI1(epithelial-stromal interaction 1), one of IL-28A-induced ISGs, plays a vital role in IL28A-mediated antiviral activity. Furthermore, forced expression of EPSTI1 effectively inhibits HCV replication in the absence of interferon treatment, and knockdown of EPSTI1 contributes to viral enhancement. EPSTI1 can activate PKR promoter and induce several PKR-dependent genes, including IFN-β, IFIT1, OAS1 and RNase L, which is responsible for EPSTI1-mediated antiviral activity. These data suggest that EPSTI1 is involved in IL28A-mediated antiviral activity via induction of PKR-dependent genes.