Cytomegalovirus Immediate Early Proteins and Virion RNAs

人巨细胞病毒（HCMV）是β-疱疹病毒家族的典型成员。流行病学 研究表明HCMV感染是广泛的。在健康个体中，感染通常是 无症状，但该病毒可导致严重的疾病，在人与不成熟或受损的免疫 系统.它是导致出生缺陷（主要是听力损失）的主要传染病， 移植受者中的威胁性外源因子。这项研究计划的长期目标是 阐明调节病毒与其宿主细胞相互作用的HCMV基因的功能， 控制病毒复制和发病机制。该计划将研究HCMV立即早期基因产物。 这些蛋白质和RNA有可能对病毒-宿主相互作用产生深远的影响，因为 它们出现在感染过程的最开始。这是一个更新应用程序，建立在我们的 最近的进展表明，UL 123编码的IE 1蛋白控制蛋白质的乙酰化， 揭示了IRS 1/TRS 1蛋白对病毒mRNA的表达具有深远的影响， 证明了所谓的5 kb RNA是一个稳定的内含子。我现在建议扩展这些意见。我 本研究的目的是研究（1）HCMV UL 122编码的IE 1蛋白的功能和生物活性; (2)HCMV IRS 1/TRS 1蛋白;和（3）HCMV 5 kb转录结构域及其MCMV直向同源物， 7.2kb转录本结构域。该项目将包括对实验室菌株（AD 169）和临床分离株的分析 （VR1814，FIX）。将在成纤维细胞中研究HCMV的复制，成纤维细胞通常用于 增殖HCMV;内皮细胞和上皮细胞。

Human cytomegalovirus (HCMV) is the prototypical member of the beta-herpesvirus family. Epidemiological studies have shown that HCMV infection is widespread. In healthy individuals infection is generally asymptomatic, but the virus can cause serious disease in people with immature or compromised immune systems. It is the leading infectious disease cause of birth defects (primarily hearing loss) and a life- threatening adventitious agent in transplant recipients. The long-term objective of this research program is to elucidate the function of HCMV genes that regulate the interaction of the virus with its host cell and thereby control viral replication and pathogenesis. This proposal will study HCMV immediate-early gene products. These proteins and RNAs have the potential to exert profound effects on the virus-host interaction, because they are present at the very start of the infectious process. This is a renewal application that builds on our recent progress, which indicates that the UL123-coded IE1 protein controls the acetylation of proteins, reveals that the IRS1/TRS1 proteins have profound effects on the expression of viral mRNAs, and demonstrates that the so-called 5kb RNA is a stable intron. I now propose to extend these observations. My specific aims investigate the function and biochemical activities of (1) the HCMV UL122-coded IE1 protein; (2) the HCMV IRS1/TRS1 proteins; and (3) the HCMV 5kb transcript domain and its MCMV orthologue, the 7.2kb transcript domain. This project will include analysis of a laboratory strain (AD169) and a clinical isolate (VR1814, FIX) of HCMV. HCMV replication will be studied in fibroblasts, the cell commonly used to propagate HCMV; endothelial cells and epithelial cells.