Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 102, Issue 8, Pages 2986-2991Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0408707102
Keywords
interferon; protease; host response; infection; NF-kappa B
Categories
Funding
- NIAID NIH HHS [AI060389, U19-AI40035, R56 AI060389, U01 AI048235, R01 AI060389, U19 AI040035, AI48235, T32 AI 07520, T32 AI007520] Funding Source: Medline
- NIDA NIH HHS [R21 DA018054, R21-DA018054] Funding Source: Medline
- NIGMS NIH HHS [T32 GM008203, T32-GM08203] Funding Source: Medline
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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 alpha/beta-IFN innate immune defenses. We demonstrate that disruption of retinoic acid-inducible gene I (RIG-1) signaling by the viral NS3/4A protease contributes to the ability of HCV to control innate antiviral defenses. RIG-1 was essential for virus or HCV RNA-induced signaling to the IFN-beta 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-kappaB 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, INS3/4A control of RIG-I supports HCV persistence by preventing IFN regulatory factor 3 and NF-kappaB activation. Our results demonstrate that these processes are amenable to restoration through pharmacologic inhibition of viral protease function.
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