Frolova Elena I, Fayzulin Rafik Z, Cook Susan H, Griffin Diane E, Rice Charles M, Frolov Ilya
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555-1019, USA.
J Virol. 2002 Nov;76(22):11254-64. doi: 10.1128/jvi.76.22.11254-11264.2002.
Alphaviruses productively infect a variety of vertebrate and insect cell lines. In vertebrate cells, Sindbis virus redirects cellular processes to meet the needs of virus propagation. At the same time, cells respond to virus replication by downregulating virus growth and preventing dissemination of the infection. The balance between these two mechanisms determines the outcome of infection at the cellular and organismal levels. In this report, we demonstrate that a viral nonstructural protein, nsP2, is a significant regulator of Sindbis virus-host cell interactions. This protein not only is a component of the replicative enzyme complex required for replication and transcription of viral RNAs but also plays a role in suppressing the antiviral response in Sindbis virus-infected cells. nsP2 most likely acts by decreasing interferon (IFN) production and minimizing virus visibility. Infection of murine cells with Sindbis virus expressing a mutant nsP2 leads to higher levels of IFN secretion and the activation of 170 cellular genes that are induced by IFN and/or virus replication. Secreted IFN protects naive cells against Sindbis virus infection and also stops viral replication in productively infected cells. Mutations in nsP2 can also attenuate Sindbis virus cytopathogenicity. Such mutants can persist in mammalian cells with defects in the alpha/beta IFN (IFN-alpha/beta) system or when IFN activity is neutralized by anti-IFN-alpha/beta antibodies. These findings provide new insight into the alphavirus-host cell interaction and have implications for the development of improved alphavirus expression systems with better antigen-presenting potential.
甲病毒能有效感染多种脊椎动物和昆虫细胞系。在脊椎动物细胞中，辛德毕斯病毒会改变细胞进程以满足病毒繁殖的需求。与此同时，细胞通过下调病毒生长和阻止感染扩散来应对病毒复制。这两种机制之间的平衡决定了在细胞和机体水平上感染的结果。在本报告中，我们证明病毒非结构蛋白nsP2是辛德毕斯病毒与宿主细胞相互作用的重要调节因子。该蛋白不仅是病毒RNA复制和转录所需的复制酶复合物的组成部分，还在抑制辛德毕斯病毒感染细胞中的抗病毒反应中发挥作用。nsP2很可能通过减少干扰素（IFN）的产生和降低病毒可见性来发挥作用。用表达突变型nsP2的辛德毕斯病毒感染鼠细胞会导致更高水平的IFN分泌以及170个由IFN和/或病毒复制诱导的细胞基因的激活。分泌的IFN可保护未感染细胞免受辛德毕斯病毒感染，也能阻止已感染细胞中的病毒复制。nsP2中的突变还可减弱辛德毕斯病毒的细胞致病性。这类突变体可在α/β干扰素（IFN-α/β）系统存在缺陷的哺乳动物细胞中持续存在，或者在IFN活性被抗IFN-α/β抗体中和时持续存在。这些发现为甲病毒与宿主细胞的相互作用提供了新的见解，并对开发具有更好抗原呈递潜力的改良甲病毒表达系统具有启示意义。
