The herpes simplex virus type 1 vhs-UL41 gene secures viral replication by temporarily evading apoptotic cellular response to infection: Vhs-UL41 activity might require interactions with elements of cellular mRNA degradation machinery
The herpes simplex virus type 1 vhs-UL41 gene secures viral replication by temporarily evading apoptotic cellular response to infection: Vhs-UL41 activity might require interactions with elements of cellular mRNA degradation machinery
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DOI：
10.1128/jvi.80.1.505-513.2006
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发表时间：
2006-01-01
影响因子：
5.4
通讯作者：
Frenkel, N
中科院分区：
文献类型：
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作者：
Barzilai, A;Zivony-Elbom, I;Frenkel, N
我们以前已经表明，单纯疱疹病毒1型（HSV-1）感染与感染细胞mRNA的早期不稳定/降解和随后通过病毒体相关宿主关闭（vhs）UL 41蛋白的活性关闭宿主蛋白质合成有关。野生型（wt）病毒不稳定/降解管家P-肌动蛋白和et-微管蛋白mRNA以及宿主应激功能，如感染后诱导的热休克70蛋白。vhs突变体不降解mRNA。其他人的详细研究关注mRNA降解的模式和受影响的mRNA。我们现在描述的VHS活动在原代培养的小鼠小脑颗粒神经元（CGNs）。具体地，（i）在放线菌素D存在下感染以测试输入病毒颗粒的活性时，存在蛋白质合成的普遍抑制，这取决于输入感染复数（MOI）。(ii)低MOI感染与VHS-1突变体病毒与所有明显的蛋白质的合成增加。较高的MOI引起一些关闭，尽管显著低于wt病毒。这种模式可以反映vhs-1蛋白与参与细胞mRNA不稳定/降解的宿主机制的相互作用，从而隔离这种活性。(iii)WT病毒感染与细胞存活相关，至少在一段时间内，而突变病毒在更早的时间诱导凋亡性细胞死亡。(iv)wt病毒在CGN中复制良好，而vhs-1突变病毒没有明显的复制。(v)vhs-1突变体可作为携带标记基因和人p53基因的复合扩增子载体的辅助病毒。正在进行的研究测试使用vhs-1为基础的复合溶瘤载体对癌症基因治疗。
We have previously shown that herpes simplex virus type 1 (HSV-1) infection is associated with early destabilization/degradation of infected cell mRNAs and consequent shutoff of host protein synthesis by the activity of the virion-associated host shutoff (vhs) UL41 protein. Wild-type (wt) virus destabilized/degraded the housekeeping P-actin and et-tubulin mRNAs as well host stress functions, like the heat shock 70 protein induced postinfection. vhs mutants did not degrade the mRNAs. Elaborate studies by others have been concerned with the mode of mRNA degradation and the mRNAs affected. We now describe vhs activity in primary cultures of mouse cerebellar granule neurons (CGNs). Specifically, (i) upon infection in the presence of actinomycin D to test activity of input viral particles, there was a generalized inhibition of protein synthesis, which depended on the input multiplicity of infection (MOI). (ii) Low-MOI infection with vhs-1 mutant virus was associated with increased synthesis of all apparent proteins. Higher MOIs caused some shutoff, albeit significantly lower than that of wt virus. This pattern could reflect an interaction(s) of vhs-1 protein with host machinery involved in cellular mRNA destabilization/degradation, sequestering this activity. (iii) wt virus infection was associated with cell survival, at least for a while, whereas mutant virus induced apoptotic cell death at earlier times. (iv) wt virus replicated well in the CGNs, whereas there was no apparent replication of the vhs-1 mutant virus. (v) The vhs-1 mutant could serve as helper virus for composite amplicon vectors carrying marker genes and the human p53 gene. Ongoing studies test the use of vhs-1-based composite oncolytic vectors towards cancer gene therapy.