Molecular Genetics of HSV Reactivation

描述：(申请人提供)：疱疹病毒无处不在 对重大的人类死亡和痛苦负有责任 最初的感染和(更严重的)复发。此外，随着越来越多的 免疫抑制紊乱的发生，相应地增加了 临床显著的初始和潜伏疱疹病毒感染的频率 站起来。因此，这一项目的长期目标是获得 潜伏期中疱疹病毒编码基因的功能理解 和重新激活-这是合理设计的基础知识 介入疗法。我们已经确定了基因组中的一个区域，称为 肾上腺素诱导所需的“再激活临界区”(RCR) 重新激活。这项提案的主要焦点是将 单纯疱疹病毒1型RCR中的功能角色序列元件 (HSV-1)基因组在感觉神经节潜伏感染的再激活中的作用 神经元。 这项研究的压倒一切的假设是HSV RCR促进了 通过调节潜伏基因组中的基因表达来重新激活 在重新激活过程中启动急性基因表达。使用分子 涉及特定工程病毒重组体的遗传方法，我们将 遵循HSV-1重新激活的转录和复制过程 兔角膜-肾上腺素模型将病毒遗传学与发病过程联系起来 动物。具体地说，拟议的研究将测试三个潜在的 RCR用于促进重新激活的机制：a)RCR 作为转录的调节器，通过以下方式促进重新激活 调节LAT、ICPO和/或ICP4的表达，b)RCR是 甲基化和/或在潜伏期调节转录的细胞因子 和重新激活，以及c)RCR充当非编码功能RNA，其 通过一种类似剂量补偿的机制调节基因表达。这三个人 机制并不是相互排斥的，它很可能是 这些监管要素对于维持和重新激活是必要的 从延迟开始。这项工作将导致确定病毒靶标(S)的 传递压力刺激导致重新激活的宿主因素。

DESCRIPTION:(provided by applicant): Herpesviruses are ubiquitous and are responsible for significant human mortality and suffering both in terms of initial infections and (even more so) recurrences. In addition, with increasing occurrences of immunosuppressive disorders, a corresponding increase in the frequency of clinically significant initial and latent herpesvirus infections arise. Therefore, the long-term objective of this project is to gain a functional understanding of the herpesvinis-encoded genes involved in latency and reactivation - knowledge that is fundamental to the rational design of interventive therapies. We have identified a region of the genome termed the "reactivation critical region" (rcr) that is required for epinephrine-induced reactivation. The primary focus of this proposal is to characterize the functional role sequence elements in the rcr of the Herpes simplex virus type 1 (HSV- 1) genome play in reactivation of infections latent in sensory ganglia neurons. The overriding hypothesis of this study is that the HSV rcr facilitates reactivation by regulating gene expression from the latent genome allowing the initiation of acute gene expression during reactivation. Using a molecular genetic approach involving specifically engineered viral recombinants, we will follow the transcriptional and replicative processes of HSV- 1 reactivation in the rabbit cornea-epinephrine model to link viral genetics with processes in animals. Specifically, the proposed studies will test three potential mechanisms by which the rcr functions to facilitate reactivation: a) the rcr acts as a modulator of transcription which facilitates reactivation by regulating the expression of LAT, ICPO and/or ICP4, b) the rcr is a target of methylation and/or cellular factors that regulate transcription during latency and reactivation, and c) the rcr acts as a non-coding functional RNA that regulates gene expression via a dosage compensation-like mechanism. These three mechanisms are not mutually exclusive and it is likely an interplay between these regulatory elements is necessary for the maintenance of and reactivation from latency. This work will lead to the identification of viral target(s) of host factors that communicate stress stimuli leading to reactivation.