Regulation of hepatitis C virus replication by interferon regulatory factor 1
Regulation of hepatitis C virus replication by interferon regulatory factor 1
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DOI：
10.1128/jvi.78.18.9713-9720.2004
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发表时间：
2004-09-01
影响因子：
5.4
通讯作者：
Watanabe, M
中科院分区：
文献类型：
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作者：
Kanazawa, N;Kurosaki, M;Watanabe, M
细胞抗病毒反应部分由干扰素刺激基因的表达介导，由病毒基因组、转录本和复制中间体触发。丙型肝炎病毒（HCV）复制子的持续复制表明复制子不会引起细胞先天抗病毒反应。在本研究中，我们研究了表达HCV复制子的细胞中干扰素介导的抗病毒系统的调节因子。荧光素酶报告基因分析显示，在含有复制子的细胞中，干扰素刺激反应元件（ISRE）的基线活性明显低于未处理细胞。在参与IFN/jak/STAT通路和ISRE活性的蛋白中，干扰素调节因子1 （IRF-1）的表达水平在含有该复制子的细胞中显著降低。将IRF-1表达构建体转染到含有复制子的细胞中，会导致ISRE活性增加，同时抑制HCV复制子的表达。此外，在消除HCV复制子的治愈Huh7细胞中，IRF-1的表达水平和ISRE活性也受到抑制，这表明IRF-1的降低不是由于病毒蛋白的主动抑制，而是由于细胞的适应性使HCV亚基因组能够复制。通过转基因补充IRF-1表达，消除了固化细胞对复制子的高度许可性。综上所述，IRF-1是通过调节干扰素刺激基因介导的抗病毒反应来调节细胞内HCV复制的关键宿主因子之一。
Cellular antiviral responses are mediated partly by the expression of interferon-stimulated genes, triggered by viral genomes, their transcripts and replicative intermediates. Persistent replication of a hepatitis C virus (HCV) replicon suggests that the replicon does not elicit cellular innate antiviral responses. In the present study, we investigated regulatory factors of the interferon-mediated antiviral system in cells expressing an HCV replicon. Luciferase reporter assays revealed that the baseline activity of the interferon-stimulated response element (ISRE) was significantly lower in cells harboring the replicon than in naive cells. Among the proteins involved in the IFN/jak/STAT pathway and in ISRE activity, the expression level of interferon regulatory factor 1 (IRF-1) was found to be significantly lower in cells harboring the replicon. Transfection of an IRF-1 expression construct into cells harboring the replicon caused an increase of ISRE activity, accompanied by suppression of expression of the HCV replicon. Moreover, in cured Huh7 cells from which the HCV replicon had been eliminated, the expression levels of IRF-1 and ISRE activity also were suppressed, demonstrating that the decrease of IRF-1 is attributable, not to active suppression by the viral proteins, but to adaptation of cells that enables replication of the HCV subgenome. The high permissiveness of the cured cells for the replicon was abolished by transgenic supplementation of IRF-1 expression. Taken together, IRF-1 is one of the key host factors that regulate intracellular HCV replication through modulation of interferon-stimulated-gene-mediated antiviral responses.