ROLE OF THE LAT-ICP0 LOCUS IN REGULATING HSV LATENCY

LAT-ICP0 基因座在调节 HSV 潜伏期中的作用

• 批准号: 6678566
• 负责人: WILLIAM P HALFORD
• 金额: $ 13.61万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6678566
• 关键词: Adenoviridae; antisense nucleic acid; gene induction /repression; genetic transcription; herpes simplex virus 1; immediate early protein; laboratory mouse; latent virus infection; tissue /cell culture; transfection; trigeminal nerve; virus RNA; virus genetics

DESCRIPTION (provided by applicant): Recurrent infections with herpes simplex viruses (HSV) are a significant clinical problem. Fundamental to understanding the nature of recurrent herpetic disease is determining precisely how HSV alternates between the two phases of its dual life cycle, latency and reactivation of productive infection. The LAT-ICP0 locus plays a central role in the regulation of HSV-1 latency and reactivation. The genes that encode for the latency-associated transcripts (LATs) and infected cell polypeptide 0 (ICP0) form a continuous locus in the repeated regions of the HSV genome. Specifically, the LAT and ICP0 genes lie on opposite strands of HSV-1's double-stranded DNA genome and share a significant overlap. Thus, the abundant LATs can hybridize to 0.75 kilobases of complementary sequence in ICP0 mRNA. While the antisense arrangement of the LAT-ICP0 locus has long been recognized, the hypothesis that LAT RNAs serve as "antisense repressors" of ICP0 gene expression has not been rigorously analyzed. The juxtaposition of the LAT and ICP0 genes mirrors their opposing roles in latency. While LAT RNAs facilitate the maintenance of HSV latency, expression of ICP0 is necessary and sufficient to induce HSV-1 reactivation. Conversely, failure to express ICP0 is highly conducive to HSV genomes entering a transcriptionally repressed state. Thus, antisense repression of ICP0 mRNA translation is one mechanism by which LATs may facilitate the maintenance of latency. The goal of this research proposal is to evaluate the concept that LAT RNAs and ICP0 form a pair of mutually dependent, opposite regulators that are the yin and yang of HSV latency. Specifically, genetic evidence will be obtained to test the hypothesis that "All viral proteins that induce HSV-1 reactivation in the trigeminal ganglion cell culture model achieve this phenotype via (a) induction of ICP0, (b) suppression of LAT transcription, or (c) both."

描述（由申请人提供）：单纯疱疹病毒（HSV）的反复感染是一​​个重要的临床问题。了解复发性疱疹疾病本质的基础是准确确定 HSV 如何在其双重生命周期的两个阶段（生产性感染的潜伏期和重新激活）之间交替。 LAT-ICP0 基因座在 HSV-1 潜伏期和再激活的调节中发挥着核心作用。编码潜伏相关转录本 (LAT) 和感染细胞多肽 0 (ICP0) 的基因在 HSV 基因组的重复区域中形成连续基因座。具体来说，LAT 和 ICP0 基因位于 HSV-1 双链 DNA 基因组的相反链上，并且具有显着的重叠。因此，丰富的 LAT 可以与 ICP0 mRNA 中 0.75 kb 的互补序列杂交。虽然 LAT-ICP0 基因座的反义排列早已被认识，但 LAT RNA 作为 ICP0 基因表达的“反义阻遏物”的假设尚未得到严格分析。 LAT 和 ICP0 基因的并置反映了它们在潜伏期中相反的作用。虽然 LAT RNA 有助于维持 HSV 潜伏期，但 ICP0 的表达对于诱导 HSV-1 重新激活是必要且充分的。相反，ICP0 表达失败非常有利于 HSV 基因组进入转录抑制状态。因此，ICP0 mRNA 翻译的反义抑制是 LAT 可能促进潜伏期维持的一种机制。本研究计划的目标是评估 LAT RNA 和 ICP0 形成一对相互依赖、相反的调节因子（HSV 潜伏期的阴阳）的概念。具体来说，将获得遗传证据来检验以下假设：“在三叉神经节细胞培养模型中诱导 HSV-1 重新激活的所有病毒蛋白均通过 (a) 诱导 ICP0、(b) 抑制 LAT 转录或 (c) 两者实现此表型。”