Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling.
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-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-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, NS3/4A 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.
Foy
Eileen
E
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Li
Kui
K
Sumpter
Rhea
R
Loo
Yueh-Ming
YM
Johnson
Cynthia L
CL
Wang
Chunfu
C
Fish
Penny Mar
PM
Yoneyama
Mitsutoshi
M
Fujita
Takashi
T
Lemon
Stanley M
SM
Gale
Michael
M
D045744:Cell Line, Tumor; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D016174:Hepacivirus / Q000276:immunology* / Q000502:physiology; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D020365:RNA Helicases / Q000502:physiology*; D011971:Receptors, Immunologic; D015398:Signal Transduction / Q000502:physiology*; D017361:Viral Nonstructural Proteins / Q000502:physiology*; D014779:Virus Replication; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D000085242:Viral Proteases
D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D016328:NF-kappa B; D020365:RNA Helicases; D011971:Receptors, Immunologic; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D000085242:Viral Proteases; C093542:NS4 protein, hepatitis C virus; C452820:RIGI protein, human