Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling
Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signaling
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DOI：
10.1073/pnas.0408707102
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发表时间：
2005-02-22
影响因子：
11.1
通讯作者：
Gale, M
中科院分区：
文献类型：
--
作者：
Foy, E;Li, K;Gale, M
丙型肝炎病毒（HCV）是一种主要的人类病原体，感染了1.7亿人。HCV的标志是其建立持续感染的能力，反映了逃避宿主免疫和干扰α/β-IFN先天免疫防御。我们证明，破坏维甲酸诱导基因I（RIG-1）信号的病毒NS 3/4A蛋白酶的HCV控制先天性抗病毒防御的能力。RIG-1对于病毒或HCV RNA诱导的人肝癌细胞中IFN-β启动子的信号传导是必需的。这种信号传导被NS 3/4A的蛋白酶活性破坏，其消除下游IFN调节因子3的RIG-I信号传导和NF-κ B活化，减弱宿主抗病毒防御基因的表达并中断IFN扩增环，否则IFN扩增环抑制HCV复制。用NS 3/4A蛋白酶的活性位点抑制剂处理细胞缓解了这种抑制并恢复了细胞内的抗病毒防御。因此，RIG-I的INS 3/4A控制通过阻止IFN调节因子3和NF-κ B活化来支持HCV持续存在。我们的研究结果表明，这些过程是适合通过药物抑制病毒蛋白酶功能的恢复。
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.