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J Hepatol. 2011 Aug;55(2):289-98. doi: 10.1016/j.jhep.2010.11.019. Epub 2010 Dec 13.

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

Author information

  • 1Gastrointestinal Unit, Department of Medicine, Warren 1007, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. armzhang@hotmail.com

Abstract

BACKGROUND & AIMS:

The combination of pegylated interferon (IFN) α 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 IFNλ3, 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 Jc1, we assessed the anti-HCV effect of IL28B on HCV and characterized the key steps of the JAK-STAT pathway by real time PCR, luciferase assay, and Western blot. Finally, we evaluated the anti-HCV effect of IL28B in the presence of JAK-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 IFNα, 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 JAK-STAT pathway to inhibit HCV. These data suggest possible applications of new approaches in HCV treatment.

Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

PMID:
21147189
[PubMed - indexed for MEDLINE]
PMCID:
PMC3068235
Free PMC Article

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