Virus Host Interactions that Regulate Translation in Cells Infected with HSV-1

mRNA翻译的一个关键步骤是将40S核糖体亚基募集到带帽转录本的5'端。通常，多亚基翻译起始因子的集合执行此任务。病毒为研究这一基本过程提供了有吸引力的模型系统，因为它们是专性细胞内寄生虫，完全依赖于宿主体内的蛋白质合成机制。由于mRNA翻译是病毒复制的必要条件，病毒不仅精通操纵宿主细胞的翻译机制，而且有效地控制调节蛋白质合成的细胞信号通路。本研究的重点是单纯疱疹病毒-1 (HSV-1)，这是一种神经营养性疱疹病毒，其多产性复制可导致一系列人类疾病，从免疫功能正常宿主的自限性上皮溃疡、严重眼病和危及生命的脑炎，到新生儿和免疫功能低下个体的播散性疾病。我们的长期目标是了解HSV-1如何通过改变和重塑细胞和病毒多肽生产所需的翻译起始因子复合物，成功地参与和控制细胞蛋白质合成装置。由于这一过程对于潜伏期和无性病毒生长的再激活至关重要，我们的分析可能会发现潜在治疗干预的新靶点。我们特别建议：(1)了解细胞翻译因子复合物因HSV-1感染而改变的机制；ii)研究细胞翻译抑制因子4E结合蛋白-1在HSV-1感染细胞中的调控机制；iii)确定HSV-1如何操纵细胞激酶mTOR以适当控制病毒蛋白合成。

A critical step in mRNA translation involves the recruitment of the 40S ribosome subunit to the 5' end of capped transcripts. Typically, an ensemble of multi-subunit translation initiation factors executes this task. Viruses provide attractive model systems to study this fundamental process, as they are obligate intracellular parasites, completely dependent upon the protein synthesis machinery resident in their hosts. As mRNA translation is necessary for their replication, viruses are proficient in manipulating not only the host cell translational machinery, but also effectively commandeer the cellular signaling pathways that regulate protein synthesis. This investigation concentrates on Herpes simplex virus-1 (HSV-1), a neurotrophic herpesvirus whose productive replication is responsible for a spectrum of human diseases ranging from self- limiting epithelial sores, severe ocular disease and life threatening encephalitis in immunocompetent hosts to disseminated disease in neonates and immunocompromised individuals. Our long - term objective is to understand how HSV-1 successfully engages and controls the cellular protein synthesis apparatus by both altering and remodeling translation initiation factor complexes required for the production of both cellular and viral polypeptides. As this process is of vital importance for reactivation from latency and vegetative viral growth, our analysis is likely to uncover new targets for potential therapeutic intervention. We specifically propose to i) understand the mechanism(s) whereby cellular translation factor complexes are altered as a result of HSV-1 infection; ii) investigate how the cellular translation repressor 4E- binding protein-1 is controlled in HSV-1 infected cells; and iii) determine how HSV-1 manipulates the cellular kinase mTOR to properly control viral protein synthesis.