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Immediate Early Genes of Herpes Simplex Virus

单纯疱疹病毒的早期基因

基本信息

批准号：
7426451
负责人：
RYAN M BRINGHURST
金额：
$ 38.76万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
1980
资助国家：
美国
起止时间：
1980-03-01 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7426451
关键词：
Activities of Daily Living Affect Afferent Neurons Cell Cycle Cell Cycle Progression Cells Computer Simulation Cultured Cells Cyclin-Dependent Kinases Cyclins Environment Epithelial Cells Fibroblasts Funding Gene Expression Genes Genetic Transcription Growth Herpesvirus 1 Human Immediate-Early Genes Immediate-Early Proteins In Vitro Individual Infection Lead Life Life Cycle Stages Light Maintenance Measures Molecular Mus Mutate Mutation Neurons Nuclear Peptides Phosphorylation Phosphorylation Site Phosphotransferases Plasmids Proteins Purpose RNA Polymerase II Reporter Research Personnel Simplexvirus Site Specific qualifier value Staging Stimulus Stress Testing Transport Process Viral Viral Genome Viral Pathogenesis Viral Proteins Virus Virus Diseases base cell type cytotoxicity insight latent infection mouse model mutant novel strategies programs protein function reactivation from latency response sorcin transcription factor

项目摘要

DESCRIPTION (provided by applicant): Herpes simplex virus 1 (HSV-1) establishes life-long infections of the human host characterized by productive infection of actively cycling epithelial cells and fibroblasts, and nonproductive latent infections of noncycling sensory neurons. Latent infections are characterized by the reactivation of productive cycle viral gene expression and new virus synthesis following stress. During the early stages of productive infection, viral immediate-early (IE) proteins act together to create a nuclear environment that promotes viral gene expression. Available evidence indicates that the phosphorylation of IE proteins by cyclin dependent kinases (cdks), other cellular kinases and viral kinases is responsible for the timely activation of IE protein functions. The expression of kinase activities in cycling cells during productive infection, the absence of these activities in noncycling latently infected neurons, and their induction in noncycling neurons following stress-induced reactivation, has led to the hypothesis that productive infection, reactivation and the activities of IE proteins are associated with the activities of these cdks and other kinases whereas latency is associated with their absence. Among HSV IE proteins, ICP0, ICP22 and ppUS1.5 have been shown to affect and be affected by cdks and their cyclin partners. These proteins confer a significant growth advantage on HSV-1 and are required for the efficient establishment and reactivation of latency. This proposal will test the hypothesis that the phosphorylation of ICP0, ICP22 and ppUS1.5 by cdks and other kinases expressed differentially in nonneuronal and neuronal cells affects the functional capabilities of these proteins during productive infection, latency and reactivation. For this purpose we will i) identify the sites on ICP0, ICP22 and ppUS1.5 that are phosphorylated and the cdks and other kinases that phosphorylate these sites, ii) test the effects of phosphorylation at selected sites by specific kinases on the functions of ICP0, ICP22 and ppUS1.5 in cell culture and during productive infection and latency and iii) examine the molecular basis for the ability of ICP22 and/or ppUSl.5 and phosphorylation site mutants thereof to inhibit the functions of ICP0. The information obtained in these studies will provide new insight into the molecular mechanism underlying HSV- 1 productive infection and latency and lead to novel approaches to intervening in the life-cycle of this clinically important virus.

描述（由申请方提供）：单纯疱疹病毒1型（HSV-1）确立了人类宿主的终身感染，其特征为活跃循环上皮细胞和成纤维细胞的生产性感染，以及非循环感觉神经元的非生产性潜伏感染。潜伏性感染的特征在于应激后生产性周期病毒基因表达的再激活和新病毒的合成。在生产性感染的早期阶段，病毒立即早期（IE）蛋白共同作用，创造一个促进病毒基因表达的核环境。现有证据表明，细胞周期蛋白依赖性激酶（cdks）、其他细胞激酶和病毒激酶对IE蛋白的磷酸化是IE蛋白功能及时激活的原因。在生产性感染，这些活动的情况下，在noncycling潜伏感染的神经元，并在noncycling神经元的诱导应激诱导的再激活过程中，在循环细胞中的激酶活性的表达，导致了生产性感染，再激活和IE蛋白的活动与这些cdks和其他激酶的活动，而潜伏期与他们的缺席。在HSV IE蛋白中，ICP 0、ICP 22和ppUS1.5已显示影响cdks及其细胞周期蛋白伴侣并受其影响。这些蛋白质赋予HSV-1显著的生长优势，并且是有效建立和重新激活潜伏期所需的。该提案将检验以下假设：在非神经元和神经元细胞中差异表达的cdks和其他激酶对ICP 0、ICP 22和ppUS1.5的磷酸化影响这些蛋白质在生产性感染、潜伏期和再激活期间的功能能力。为此目的，我们将i）鉴定ICP 0、ICP 22和ppUS 1.5上被磷酸化的位点以及使这些位点磷酸化的cdk和其它激酶，ii）测试特定激酶在所选位点的磷酸化对ICP 0功能的影响，ICP 22和ppUS 1.5在细胞培养物中和在生产性感染和潜伏期期间的能力，和iii）检查ICP 22和/或ppUS 1.5在细胞培养物中和在生产性感染和潜伏期期间的能力的分子基础。或ppUS1.5及其磷酸化位点突变体，以抑制ICP 0的功能。这些研究中获得的信息将为HSV- 1产生性感染和潜伏期的分子机制提供新的见解，并导致干预这种临床重要病毒生命周期的新方法。