IL28B inhibits hepatitis C virus replication through the JAK-STAT pathway

Background 8: Aims: The combination of pegylated interferon (IFN) alpha and ribavirin (RBV) is the standard therapy for patients with chronic HCV infection. However, it produces a sustained virologic response (SVR) in only half of the treated individuals and is associated with significant side effects. Recently, several single-nucleotide polymorphisms (SNPs) near the IL28B locus, also known as IFN lambda 3, were identified to be strong predictors of SVR in patients receiving PEG-IFN and RBV. We sought to determine whether IL28B was capable of inhibiting HCV replication and to determine the pathway by which IL28B exhibits anti-HCV activity. Methods: Using the full-length HCV replicon OR6 and the infectious HCV clones JFH1 and El, we assessed the anti-HCV effect of IL28B on HCV and characterized the key steps of the JAR-STAT pathway by real time PCR, luciferase assay, and Western blot. Finally, we evaluated the anti-HCV effect of IL28B in the presence of JAR-STAT pathway inhibitors such as blocking antibodies, a pharmacological inhibitor, and siRNAs. Results: We found that IL28B inhibits HCV replication in a dose- and time-dependent manner. Like IFN alpha, IL28B induces the phosphorylation of STAT1 and STAT2, ISRE-driven transcription, and expression of known ISGs. The anti-HCV effects of IL28A, IL28B, and IL29 were abrogated by an IL10R2 blocking antibody, a pharmacological inhibitor of JAK1/TYK2, and by siRNA against IL28R1, STAT1, STAT2, and IRF9. Conclusions: Our data demonstrate that IL28A, IL28B, and IL29 signal through the JAR-STAT pathway to inhibit HCV. These data suggest possible applications of new approaches in HCV treatment. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.