Both Cyclophilin Inhibitors and Direct-Acting Antivirals Prevent PKR Activation in HCV-Infected Cells.

The Open Virology Journal Pub Date : 2014-03-07 eCollection Date: 2014-01-01 DOI:10.2174/1874357901408010001
Michael Bobardt, Udayan Chatterji, Precious Lim, Katarzyna Gawlik, Philippe Gallay
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引用次数: 7

Abstract

We and others demonstrated that the contact between NS5A and the host factor CypA is critical for HCV replication. CypI, by disrupting NS5A-CypA complexes, block HCV replication both in vitro and in patients. Since NS5A also binds to PKR, a central component of the IFN response, we investigated the possibility of a relationship between CypA, NS5A and PKR in the IFN response to HCV. HCV-infected cells treated with CypI, DAAs or IFN were analyzed for the expression and activation of various components of the innate response. We found that CypI (cyclosporine A, alisporivir, NIM811 and sanglifehrins), drastically prevented the activation/phosphorylation, but not the expression of IFN-induced PKR in HCV-infected cells. CypI had no effect on the expression or phosphorylation of other components of the innate response such as eiF2, NF-kB, IRF3, IRF9, STAT1 and STAT2, suggesting a specific effect on PKR. No significant activation of IFN-induced PKR was observed in the absence of HCV. Importantly, we found that several classes of DAAs such as NS3/4A protease, NS5B polymerase and NS5A inhibitors also prevented PKR activation. Furthermore, we found that PKR activation by the dsRNA mimic poly I:C cannot be prevented by CypI or DAAs. Our findings suggest that CypI do not have a unique effect on PKR activation, but rather the suppression of HCV replication by any anti-HCV inhibitor, abrogates PKR activation induced by IFN. Moreover, they suggest that the accumulation of dsRNA intermediates allows HCV to exploit the activation of PKR to counteract the IFN response.

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亲环蛋白抑制剂和直接作用抗病毒药物均可阻止hcv感染细胞中PKR的激活。
我们和其他人证明NS5A和宿主因子CypA之间的接触对HCV复制至关重要。CypI通过破坏NS5A-CypA复合物,在体外和患者体内阻断HCV复制。由于NS5A也与PKR结合,PKR是IFN应答的核心组成部分,因此我们研究了CypA、NS5A和PKR在IFN对HCV应答中的关系。用CypI、DAAs或IFN处理hcv感染细胞,分析先天反应中各种成分的表达和激活。我们发现CypI (cyclosporine A, alisporivir, NIM811和sanglifehrins)可以显著阻止hcv感染细胞中ifn诱导的PKR的活化/磷酸化,但不能阻止其表达。CypI对先天应答的其他组分如eiF2、NF-kB、IRF3、IRF9、STAT1和STAT2的表达或磷酸化没有影响,这表明CypI对PKR有特异性影响。在没有HCV的情况下,没有观察到ifn诱导的PKR的显著激活。重要的是,我们发现几种daa如NS3/4A蛋白酶、NS5B聚合酶和NS5A抑制剂也能阻止PKR的激活。此外,我们发现PKR被dsRNA模拟poly I:C激活不能被CypI或DAAs阻止。我们的研究结果表明,CypI对PKR激活并没有独特的作用,而是通过任何抗HCV抑制剂抑制HCV复制,从而消除IFN诱导的PKR激活。此外,他们认为dsRNA中间体的积累允许HCV利用PKR的激活来抵消IFN的反应。
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