Gorchakov Rodion, Frolova Elena, Frolov Ilya
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, 77555-1019, USA.
J Virol. 2005 Aug;79(15):9397-409. doi: 10.1128/JVI.79.15.9397-9409.2005.
Alphaviruses are arthropod-borne viruses (arboviruses) that include a number of important human and animal pathogens. The natural transmission cycle of alphaviruses requires their presence at high concentrations in the blood of amplification hosts for efficient infection of mosquito vectors. The high-titer viremia development implies multiple rounds of infection that proceed in the background of the developing antiviral cell response aimed at blocking virus spread on an organismal level. Therefore, as for many viruses, if not most of them, alphaviruses have evolved mechanisms directed toward downregulating different components of the antiviral cell reaction and increasing viremia to a level sufficient for the next round of transmission. Using Sindbis virus (SIN) as a model, we demonstrated that (i) the replication of wild-type SIN strongly affects major cellular processes, e.g., transcription and translation of mRNAs; (ii) transcriptional and translational shutoffs are distinctly independent events, and their development can be differentially manipulated by creating different mutations in SIN nonstructural protein nsP2; and (iii) inhibition of transcription, but not translation, is a critical mechanism that SIN employs to suppress the expression of cellular viral stress-inducible genes in cells of vertebrate origin. Downregulation of transcription of all of the cellular mRNAs appears to be a very efficient means of reducing the development of an antiviral response. The ability to cause transcriptional shutoff may partially determine SIN host range and replication in particular tissues.
甲病毒是节肢动物传播病毒（虫媒病毒），包括许多重要的人类和动物病原体。甲病毒的自然传播循环要求它们在扩增宿主的血液中以高浓度存在，以便有效地感染蚊媒。高滴度病毒血症的发展意味着在旨在阻止病毒在机体水平传播的抗病毒细胞反应的背景下进行多轮感染。因此，与许多病毒一样（如果不是大多数病毒的话），甲病毒已经进化出一些机制，旨在下调抗病毒细胞反应的不同成分，并将病毒血症提高到足以进行下一轮传播的水平。以辛德毕斯病毒（SIN）为模型，我们证明：（i）野生型SIN的复制强烈影响主要细胞过程，如mRNA的转录和翻译；（ii）转录和翻译关闭是明显独立的事件，通过在SIN非结构蛋白nsP2中产生不同的突变，可以对它们的发展进行不同的调控；（iii）抑制转录而非翻译是SIN用于抑制脊椎动物来源细胞中细胞病毒应激诱导基因表达的关键机制。下调所有细胞mRNA的转录似乎是减少抗病毒反应发展的一种非常有效的手段。引起转录关闭的能力可能部分决定了SIN的宿主范围和在特定组织中的复制。
