Abstract :
Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling. Foy E, Li K, Sumpter R Jr, Loo YM, Johnson CL, Wang C, Fish PM, Yoneyama M, Fujita T, Lemon SM, Gale M Jr.
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) signalling 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 signalling to the IFN-β promoter in human hepatoma cells. This signalling was disrupted by the protease activity of NS3/4A, which ablates RIG-I signalling of downstream IFN regulatory factor 3 and NF-κB activation, attenuating expression of host antiviral defence 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.
[Abstract reproduced by permission of Proc Natl Acad Sci USA 2005;102:2986-91]
Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF. Li K, Foy E, Ferreon JC, Nakamura M, Ferreon ACM, Ikeda M, Ray SC, Gale M Jr, Lemon SM.
Toll-like receptors (TLRs) bind pathogen-specific ligands early in infection, initiating signalling pathways that lead to expression of multiple protective cellular genes. Many viruses have evolved strategies that block the effector mechanisms induced through these signalling pathways, but viral interference with critical proximal receptor interactions has not been described. We show here that the NS3/4A serine protease of hepatitis C virus (HCV), a virus notorious for its ability to establish persistent intrahepatic infection, causes specific proteolysis of Toll-IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF or TICAM-1), an adaptor protein linking TLR3 to kinases responsible for activating IFN regulatory factor 3 (IRF-3) and NF-κB, transcription factors controlling a multiplicity of antiviral defenses. NS3/4A-mediated cleavage of TRIF reduces its abundance and inhibits polyI:C -activated signalling through the TLR3 pathway before its bifurcation to IRF-3 and NF-κB. This uniquely broad mechanism of immune evasion potentially limits expression of multiple host defence genes, thereby promoting persistent infections with this medically important virus.
[Abstract reproduced by permission of Proc Natl Acad Sci USA 2005;102:2992-7]
