Hepatitis C virus non-structural proteins responsible for suppression of the RIG-I/Cardif-induced interferon response.
Hepatitis C virus non-structural proteins responsible for suppression of the RIG-I/Cardif-induced interferon response.
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DOI：
10.1099/vir.0.83056-0
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发表时间：
2007-12
期刊：
影响因子：
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通讯作者：
M. Tasaka;N. Sakamoto;Yoshie Itakura;M. Nakagawa;Yasuhiro Itsui;Yuko Sekine‐Osajima;Yuki Nishimura‐Sakurai;Cheng-Hsin Chen;M. Yoneyama;T. Fujita;T. Wakita;S. Maekawa;N. Enomoto;Mamoru Watanabe
中科院分区：
文献类型：
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作者：
M. Tasaka;N. Sakamoto;Yoshie Itakura;M. Nakagawa;Yasuhiro Itsui;Yuko Sekine‐Osajima;Yuki Nishimura‐Sakurai;Cheng-Hsin Chen;M. Yoneyama;T. Fujita;T. Wakita;S. Maekawa;N. Enomoto;Mamoru Watanabe
病毒感染激活I型干扰素（IFN）的细胞表达。这些反应部分由RIG-I触发，并由Cardif、TBK 1、IKK 3和IRF-3介导。本研究分析了支持亚基因组丙型肝炎病毒（HCV）复制的各种细胞系中dsRNA诱导的IFN应答的机制。如IRF-3二聚化所示，将dsRNA转染到Huh 7、HeLa和HEK 293细胞中诱导IFN表达应答，而这些应答在表达HCV复制子的相应细胞系中被消除。类似地，RIG-I依赖的IFN刺激的应答元件（ISRE）的激活被表达HCV复制子的细胞显著抑制，并在复制子消除的细胞中恢复。单个HCV非结构蛋白的过表达分析显示，NS 4 B以及NS 34 A显著抑制RIG-I触发的ISRE激活。综上所述，HCV复制和蛋白表达基本上阻断了dsRNA触发的、RIG-I介导的IFN表达应答，并且这种阻断部分由HCV NS 4 B以及NS 34 A介导。这些机制可能有助于HCV感染的临床持续性，并可能构成一个新的抗病毒治疗靶点。
Viral infections activate cellular expression of type I interferons (IFNs). These responses are partly triggered by RIG-I and mediated by Cardif, TBK1, IKKepsilon and IRF-3. This study analysed the mechanisms of dsRNA-induced IFN responses in various cell lines that supported subgenomic hepatitis C virus (HCV) replication. Transfection of dsRNA into Huh7, HeLa and HEK293 cells induced an IFN expression response as shown by IRF-3 dimerization, whilst these responses were abolished in corresponding cell lines that expressed HCV replicons. Similarly, RIG-I-dependent activation of the IFN-stimulated response element (ISRE) was significantly suppressed by cells expressing the HCV replicon and restored in replicon-eliminated cells. Overexpression analyses of individual HCV non-structural proteins revealed that NS4B, as well as NS34A, significantly inhibited RIG-I-triggered ISRE activation. Taken together, HCV replication and protein expression substantially blocked the dsRNA-triggered, RIG-I-mediated IFN expression response and this blockade was partly mediated by HCV NS4B, as well as NS34A. These mechanisms may contribute to the clinical persistence of HCV infection and could constitute a novel antiviral therapeutic target.