Ribavirin regulates hepatitis C virus replication through enhancing interferon-stimulated genes and interleukin 8.

Abstract

BACKGROUND:

The manner in which ribavirin (RBV) enhances the antiviral effects of interferon (IFN) against hepatitis C virus (HCV) remains unknown. We investigated whether RBV modifies IFN-stimulated genes (ISGs) in vivo and in vitro.

METHODS:

We measured the messenger RNA (mRNA) levels of ISGs in T lymphocytes from patients with HCV infection who were receiving IFN-α therapy with or without RBV. We added RBV and/or IFN-α to a plasmid-based HCV replication system containing a full-length HCV genotype 1a sequence in HepG2 and Huh7 cell lines and the JFH-1 HCV genotype 2a sequence in Huh7 cell lines and measured levels of ISGs and autocrine IFN-β.

RESULTS:

The expression of protein kinase R and myxovirus resistance A mRNA was enhanced more with IFN-α and RBV than by IFN-α alone in assays in vivo and in vitro. Such enhancement depended on autocrine IFN-β being enhanced by RBV. RBV upregulated interleukin 8 (IL-8) in the absence of IFN-α. The IL-8 upregulation induced by RBV was responsible for the activation of activator protein 1 (AP-1).

CONCLUSIONS:

Ribavirin augments the anti-HCV effects of IFN-α induced by ISGs through enhancing autocrine IFN-β. Moreover, RBV can enhance IL-8 through activating AP-1. Improved understanding of ISG modulation by RBV would help to establish a means of eliminating HCV.

• Authors: Yoshio Tokumoto, Yoichi Hiasa, Kazuhiro Uesugi, Takao Watanabe, Toshie Mashiba, Masanori Abe, Teru Kumagi, Yoshio Ikeda, Bunzo Matsuura, Morikazu Onji
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 205 Issue 7 Pg. 1121-30 (Apr 01 2012) ISSN: 1537-6613 [Electronic] United States
• PMID: 22357660 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• CXCL8 protein, human
• Interferon-alpha
• Interleukin-8
• Ribavirin
• Interferon-beta

Topics

• Adult
• Aged
• Antiviral Agents (administration & dosage, pharmacology)
• Female
• Gene Expression Profiling
• Hepacivirus (drug effects, growth & development, immunology)
• Hepatitis C (drug therapy, immunology, virology)
• Humans
• Interferon-alpha (administration & dosage, pharmacology)
• Interferon-beta (biosynthesis, immunology)
• Interleukin-8 (biosynthesis, immunology)
• Male
• Middle Aged
• Ribavirin (administration & dosage, pharmacology)
• T-Lymphocytes (immunology)
• Transcriptional Activation
• Virus Replication (drug effects)