Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein
Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein
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DOI：
10.1006/viro.1997.8493
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发表时间：
1997-04-14
期刊：
影响因子：
3.7
通讯作者：
Katze, MG
中科院分区：
文献类型：
--
作者：
Gale, MJ;Korth, MJ;Katze, MG
丙型肝炎病毒（HCV）是非甲非乙型肝炎的主要原因，也是全球肝功能障碍的主要原因。虽然目前慢性HCV感染的治疗是1型干扰素（IFN）的胃肠外给药，只有一小部分HCV感染的个体完全响应治疗。以前的研究已经将HCV-1b株的[IFN]敏感性与病毒非结构5A蛋白（NS 5A）的离散区域（称为干扰素敏感性决定区（ISDR））内的突变相关联，表明NS 5A可能有助于HCV的IFN抗性表型。为了确定HCV NS 5A和NS 5A ISDR在介导HCV IFN抗性中的重要性，我们测试了NS 5A蛋白是否可以调节IFN诱导的蛋白激酶PKR，PKR是IFN诱导的抗病毒抗性的介体，也是病毒和细胞抑制剂的靶标。使用多种方法，包括生物化学，转染和酵母遗传学分析，我们现在可以报告NS 5A通过与蛋白激酶催化结构域的直接相互作用抑制PKR，并且PKR抑制和相互作用都需要ISDR。因此，PKR的失活可能是HCV避免IFN抗病毒作用的一种机制。最后，NS 5A对PKR蛋白激酶的抑制是该HCV蛋白的首次描述的功能。(C)北京：科学出版社.
Hepatitis C virus (HCV) is the major cause of non-A non-B hepatitis and a leading cause of liver dysfunction worldwide. While the current therapy for chronic HCV infection is parenteral administration of type 1 interferon (IFN), only a fraction of HCV-infected individuals completely respond to treatment. Previous studies have correlated the [FN sensitivity of strain HCV-1b with mutations within a discrete region of the viral nonstructural 5A protein (NS5A), termed the interferon sensitivity determining region (ISDR), suggesting that NS5A may contribute to the IFN-resistant phenotype of HCV. To determine the importance of HCV NS5A and the NS5A ISDR in mediating HCV IFN resistance, we tested whether the NS5A protein could regulate the IFN-induced protein kinase, PKR, a mediator of IFN-induced antiviral resistance and a target of viral and cellular inhibitors. Using multiple approaches, including biochemical, transfection, and yeast genetics analyses, we can now report that NS5A represses PKR through a direct interaction with the protein kinase catalytic domain and that both PKR repression and interaction requires the ISDR. Thus, inactivation of PKR may be one mechanism by which HCV avoids the antiviral effects of IFN. Finally, the inhibition of the PKR protein kinase by NS5A is the first described function for this HCV protein. (C) 1997 Academic Press.