Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling

Eileen Foy, Kui Li, Rhea Sumpter, Yueh Ming Loo, Cynthia L. Johnson, Chunfu Wang, Penny Mar Fish, Mitsutoshi Yoneyama, Takashi Fujita, Stanley M. Lemon, Michael Gale

Research output: Contribution to journalArticle

430 Citations (Scopus)

Abstract

Hepatitis C virus (HCV) is a major human pathogen that infects 170 million people. A hallmark of HCV is its ability to establish persistent infections reflecting the evasion of host immunity and interference with α/β-IFN innate immune defenses. We demonstrate that disruption of retinoic acid-inducible gene I (RIG-I) signaling by the viral NS3/4A protease contributes to the ability of HCV to control innate antiviral defenses. RIG-I was essential for virus or HCV RNA-induced signaling to the IFN-β promoter in human hepatoma cells. This signaling was disrupted by the protease activity of NS3/4A, which ablates RIG-I signaling of downstream IFN regulatory factor 3 and NF-κB activation, attenuating expression of host antiviral defense genes and interrupting an IFN amplification loop that otherwise suppresses HCV replication. Treatment of cells with an active site inhibitor of the NS3/4A protease relieved this suppression and restored intracellular antiviral defenses. Thus, NS3/4A control of RIG-I supports HCV persistence by preventing IFN regulatory factor 3 and NF-κB activation. Our results demonstrate that these processes are amenable to restoration through pharmacologic inhibition of viral protease function.

Original languageEnglish (US)
Pages (from-to)2986-2991
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number8
DOIs
StatePublished - Feb 22 2005

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Tretinoin
Hepacivirus
Antiviral Agents
Peptide Hydrolases
Interferon Regulatory Factor-3
Genes
Virus Replication
Hepatocellular Carcinoma
Immunity
Catalytic Domain
RNA
Viruses
Infection

All Science Journal Classification (ASJC) codes

  • General

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Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling. / Foy, Eileen; Li, Kui; Sumpter, Rhea; Loo, Yueh Ming; Johnson, Cynthia L.; Wang, Chunfu; Fish, Penny Mar; Yoneyama, Mitsutoshi; Fujita, Takashi; Lemon, Stanley M.; Gale, Michael.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 8, 22.02.2005, p. 2986-2991.

Research output: Contribution to journalArticle

Foy, Eileen ; Li, Kui ; Sumpter, Rhea ; Loo, Yueh Ming ; Johnson, Cynthia L. ; Wang, Chunfu ; Fish, Penny Mar ; Yoneyama, Mitsutoshi ; Fujita, Takashi ; Lemon, Stanley M. ; Gale, Michael. / Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling. In: Proceedings of the National Academy of Sciences of the United States of America. 2005 ; Vol. 102, No. 8. pp. 2986-2991.
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