Ribavirin potentiates interferon action by augmenting interferon-stimulated gene induction in HCV cell culture models

Hepatology
Accepted Article (Accepted, unedited articles published online for future issues)

Emmanuel Thomas 1, Jordan J. Feld 1,2, Qisheng Li 1, Zongyi Hu 1, Michael W. Fried 3, T. Jake Liang 1,*
DOI: 10.1002/hep.23985
Copyright © 2010 American Association for the Study of Liver Diseases

Author Information
1 Liver Diseases Branch, NIDDK/NIH, 10 Center Dr., Building 10, 9B17, Bethesda, MD, 20892, USA
2 Toronto Western Hospital Liver Centre, Department of Medicine, Division of Gastroenterology, 6B Fell Pavillion Room 160, 399 Bathurst St, Toronto, ON M5T 2S8, Canada
3 Division of Gastroenterology and Hepatology, University of North Carolina, CB 7584, Room 8015 Burnett Womack Building, Chapel Hill, NC, 27514, USA

Email: T. Jake Liang (JakeL@bdg10.niddk.nih.gov)

* Correspondence: T. Jake Liang, Liver Diseases Branch, NIDDK/NIH, 10 Center Dr., Building 10, 9B17, Bethesda, MD, 20892, USA

Publication History
Accepted manuscript online: 14 SEP 2010 08:04AM EST
Manuscript Accepted: 4 SEP 2010
Manuscript Revised: 2 SEP 2010
Manuscript Received: 25 MAR 2010

Funded by

• The Intramural Research Program
• The National Institute of Diabetes and Digestive and Kidney Diseases
• NIH
• NIH K24 mentoring award. Grant Number: DK066144

Abstract

The combination of peginterferon and ribavirin is the standard treatment for chronic hepatitis C. Our recent clinical study suggests that ribavirin augments the induction of interferon stimulated genes (ISGs) in patients treated for HCV infection [1]. In order to further characterize the mechanisms of action of ribavirin, we examined the effect of ribavirin treatment on ISG induction in cell culture. In addition, the effect of ribavirin on infectious HCV cell culture systems was also studied. Similar to interferon-α, ribavirin potently inhibits JFH-1 infection of Huh7.5.1 cells in a dose-dependent manner, which spans the physiological concentration of ribavirin in vivo. Microarray analysis and subsequent quantitative PCR assays demonstrated that ribavirin treatment resulted in the induction of a distinct set of ISGs. These ISGs, including IRF7 and IRF9 are known to play an important role in anti-HCV responses. When ribavirin is used in conjunction with interferon, induction of specific ISGs is synergistic when compared to either drug applied separately. Direct up-regulation of these antiviral genes by ribavirin is mediated by a novel mechanism different from those associated with interferon signaling and intracellular double stranded RNA sensing pathways such as RIG-I and MDA5. RNA interference studies excluded the activation of the Toll-like receptor and NF-KappaB pathways in the action of ribavirin. In conclusion, our study suggests that ribavirin, acting via a novel innate mechanism, potentiates the anti-HCV effect of interferon. Understanding the mechanism of action of ribavirin would be valuable in identifying novel antivirals. (HEPATOLOGY 2010.)

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