Cyclophilin Inhibitors Remodel the Endoplasmic Reticulum of HCV-Infected Cells in a Unique Pattern Rendering Cells Impervious to a Reinfection.
Cyclophilin Inhibitors Remodel the Endoplasmic Reticulum of HCV-Infected Cells in a Unique Pattern Rendering Cells Impervious to a Reinfection.
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DOI：
10.1371/journal.pone.0159511
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Gallay PA
中科院分区：
文献类型：
--
作者：
Chatterji U;Bobardt M;Schaffer L;Wood M;Gallay PA
亲环素抑制剂（CypI）干扰HCV生命周期的作用机制仍然知之甚少。我们报道CypI和NS5A抑制剂（NS5Ai），而不是其他类别的抗HCV药物，防止组装的双膜囊泡（DMVs），保护复制复合物。我们证明了NS5A和异构酶亲环素A（CypA）都是DMV形成所必需的。在这里，我们研究了CypI是否介导了额外的抗病毒作用，这可以进一步解释CypI的高疗效。我们发现了CypI的独特作用。CypI重塑HCV感染细胞的内质网（ER）组织，但不重塑未感染细胞。这种效应是特异性的，因为在其他类型的抗HCV药物（包括NS5Ai）中没有观察到这种效应，并且对CypI处理的细胞的活力没有影响。由于ER是建立HCV复制复合物的平台，我们询问CypI对ER的重组是否会阻止细胞被新感染。值得注意的是，CypI处理的HCV预感染的细胞仍然完全不受再感染的影响，这表明CypI介导的ER重组防止了再感染。这种阻断不是由于残留的CypI，因为CypI抗性HCV变体也不能感染这些细胞。CypI对内质网的重组是快速和可逆的。这项研究提供了第一个证据，表明CypI触发了感染细胞的独特ER重组，使细胞暂时不受再感染的影响。这项研究进一步表明，HCV诱导的ER重排是开发新疗法的关键靶点。
The mechanisms of action by which cyclophilin inhibitors (CypI) interfere with the HCV life cycle remain poorly understood. We reported that CypI and NS5A inhibitors (NS5Ai), but not other classes of anti-HCV agents, prevent assembly of double membrane vesicles (DMVs), which protect replication complexes. We demonstrated that both NS5A and the isomerase cyclophilin A (CypA) are required for DMV formation. Here, we examined whether CypI mediate an additional antiviral effect that could further explain the high efficacy of CypI. We identified a unique action of CypI. CypI remodel the organization of the endoplasmic reticulum (ER) of HCV-infected cells, but not of uninfected cells. This effect is specific since it was not observed for other classes of anti-HCV agents including NS5Ai, and has no effect on the viability of CypI-treated cells. Since ER serves as platform for the establishment of HCV replication complexes, we asked whether the ER reorganization by CypI would prevent cells from being newly infected. Remarkably, CypI-treated HCV-pre-infected cells remain totally impervious to a reinfection, suggesting that the CypI-mediated ER reorganization prevents a reinfection. This block is not due to residual CypI since CypI-resistant HCV variants also fail to infect these cells. The ER reorganization by CypI is rapid and reversible. This study provides the first evidence that CypI trigger a unique ER reorganization of infected cells, rendering cells transiently impervious to a reinfection. This study further suggests that the HCV-induced ER rearrangement represents a key target for the development of new therapies.