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

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.

• Authors: Leiliang Zhang, Nikolaus Jilg, Run-Xuan Shao, Wenyu Lin, Dahlene N Fusco, Hong Zhao, Kaku Goto, Lee F Peng, Wen-Chi Chen, Raymond T Chung
• Journal: Journal of hepatology (J Hepatol) Vol. 55 Issue 2 Pg. 289-98 (Aug 2011) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 21147189 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Chemical References

• Antiviral Agents
• DNA Primers
• interferon-lambda, human
• IRF9 protein, human
• Interferon-Stimulated Gene Factor 3, gamma Subunit
• Interleukins
• RNA, Small Interfering
• Receptors, Interferon
• Recombinant Proteins
• STAT Transcription Factors
• STAT1 Transcription Factor
• STAT1 protein, human
• STAT2 Transcription Factor
• STAT2 protein, human
• Interferons
• JAK1 protein, human
• Janus Kinase 1
• Janus Kinases
• TYK2 Kinase
• TYK2 protein, human

Topics

• Antiviral Agents (pharmacology)
• Base Sequence
• Cell Line
• DNA Primers (genetics)
• Hepacivirus (drug effects, physiology)
• Humans
• Interferon-Stimulated Gene Factor 3, gamma Subunit (antagonists & inhibitors, genetics, metabolism)
• Interferons
• Interleukins (genetics, pharmacology)
• Janus Kinase 1 (antagonists & inhibitors, metabolism)
• Janus Kinases (antagonists & inhibitors, metabolism)
• Phosphorylation (drug effects)
• Polymorphism, Single Nucleotide
• RNA, Small Interfering (genetics)
• Receptors, Interferon (metabolism)
• Recombinant Proteins (pharmacology)
• STAT Transcription Factors (antagonists & inhibitors, metabolism)
• STAT1 Transcription Factor (antagonists & inhibitors, genetics, metabolism)
• STAT2 Transcription Factor (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction (drug effects)
• TYK2 Kinase (antagonists & inhibitors, metabolism)
• Virus Replication (drug effects, physiology)