ROLE OF THE LAT-ICP0 LOCUS IN REGULATING HSV LATENCY

描述(申请人提供)：单纯疱疹病毒反复感染 病毒(HSV)是一个重要的临床问题。理解的基础 复发性疱疹的本质是确切地决定HSV如何 在其双重生命周期的两个阶段之间交替，延迟和 再次激活生产性感染。 LAT-ICP0基因座在HSV-1潜伏期和 重新激活。编码潜伏期相关转录本的基因 (LATS)和感染细胞多肽0(ICP0)形成一个连续的基因座。 单纯疱疹病毒基因组的重复区域。具体地说，LAT和ICP0基因取决于 单纯疱疹病毒1型S的两条相对链为双链基因组，并具有显著的 重叠。因此，丰富的LAT可以与0.75kb的 ICP0基因的互补序列。而反义排列的 Lat-ICP0基因座早已被识别，LAT RNAs作为 ICP0基因表达的反义抑制物还没有得到严格的研究 分析过了。 LAT和ICP0基因的并列反映了它们在 延迟。虽然LAT RNA有助于维持HSV的潜伏期，但表达 ICP0是诱导HSV-1重新激活的必要条件和充分条件。相反， 不表达ICP0非常有利于HSV基因组进入 转录抑制状态。因此，ICP0基因的反义抑制作用 翻译是LAT可以促进维护的一种机制 延迟。这项研究提案的目标是评估LAT的概念 RNAs和ICP0形成一对相互依赖、相对的调控因子，它们是 单纯疱疹病毒潜伏期的阴阳。具体地说，基因证据将是 来检验这样一种假设：“所有诱导HSV-1的病毒蛋白 三叉神经节细胞培养模型中的重新激活实现了这一点 通过(A)诱导ICP0，(B)抑制LAT转录，或 (C)两者都有。“

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."