Elimination of hepatitis C virus from hepatocytes by a selective activation of therapeutic molecules.
Elimination of hepatitis C virus from hepatocytes by a selective activation of therapeutic molecules.
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DOI：
10.1371/journal.pone.0015967
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发表时间：
2011-01-06
期刊：
影响因子：
3.7
通讯作者：
Matsuura Y
中科院分区：
文献类型：
--
作者：
Wen X;Abe T;Kukihara H;Taguwa S;Mori Y;Tani H;Kato N;Suzuki T;Tatsumi M;Moriishi K;Matsuura Y
为了从感染的肝细胞中消除丙型肝炎病毒（HCV），我们生成了两种在感染 HCV 的细胞中特异性激活的治疗分子。干扰素 (IFN) 调节因子 7 (IRF7) 的显性活性突变体和 HCV 复制的负调节因子 VAP-C（囊泡相关膜蛋白相关蛋白亚型 C）与 IPS-1（IFNβ 启动子刺激子 1）的 C 末端区域融合，其中包括一个经过修饰位于 ER 上的 HCV 蛋白酶切割位点 膜，并分别命名为 cIRF7 和 cVAP-C。在表达 HCV 蛋白酶的细胞中，cIRF7 被裂解，加工后的片段迁移到细胞核中，在细胞核中激活各种 IFN 启动子，包括 IFNα6、IFNβ 和 IFN 刺激反应元件的启动子。通过cIRF7的表达，在HCV复制子细胞和感染HCV JFH1株(HCVcc)的细胞中观察到IFN启动子的激活和病毒RNA复制的抑制。即使在 IFN 抗性复制子细胞中，通过 cIRF7 的表达也观察到病毒 RNA 复制的抑制。 cVAP-C的表达还导致复制子和HCVcc感染细胞中HCV复制的抑制。这些结果表明，将治疗分子递送到丙型肝炎患者的肝脏中，然后选择性激活HCV感染的肝细胞中的分子，是消除HCV的可行方法。
To eliminate hepatitis C virus (HCV) from infected hepatocytes, we generated two therapeutic molecules specifically activated in cells infected with HCV. A dominant active mutant of interferon (IFN) regulatory factor 7 (IRF7) and a negative regulator of HCV replication, VAP-C (Vesicle-associated membrane protein-associated protein subtype C), were fused with the C-terminal region of IPS-1 (IFNβ promoter stimulator-1), which includes an HCV protease cleavage site that was modified to be localized on the ER membrane, and designated cIRF7 and cVAP-C, respectively. In cells expressing the HCV protease, cIRF7 was cleaved and the processed fragment was migrated into the nucleus, where it activated various IFN promoters, including promoters of IFNα6, IFNβ, and IFN stimulated response element. Activation of the IFN promoters and suppression of viral RNA replication were observed in the HCV replicon cells and in cells infected with the JFH1 strain of HCV (HCVcc) by expression of cIRF7. Suppression of viral RNA replication was observed even in the IFN-resistant replicon cells by the expression of cIRF7. Expression of the cVAP-C also resulted in suppression of HCV replication in both the replicon and HCVcc infected cells. These results suggest that delivery of the therapeutic molecules into the liver of hepatitis C patients, followed by selective activation of the molecules in HCV-infected hepatocytes, is a feasible method for eliminating HCV.
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