Prevention of VZV Reactivation

描述（由申请人提供）：水痘带状疱疹病毒（VZV）是一种普遍存在的致水痘（水痘）的嗜神经型甲疱疹病毒，沿整个神经轴潜伏于脑神经神经节、背根神经节和自主神经节。VZV再激活，主要发生在老年人和免疫功能低下的个体中，引起带状疱疹，通常随后是带状疱疹后神经痛、脊髓炎、脑膜脑炎、血管病变和眼部疾病。没有其他人类疱疹病毒能引起如此广泛的疾病。虽然在接种带状疱疹疫苗后的3年内，带状疱疹的发病率降低了51.3%，但每年仍有近40万美国人发生带状疱疹，其中约20万人经历过PHN；其他人则发展为中风、瘫痪和失明。如果能预防病毒再激活，这些神经系统疾病都不会发生。虽然VZV再激活的分子机制尚不清楚，但VZV的独特之处在于，在潜伏感染的人类神经节中检测到不少于12个VZV转录本，而所有其他嗜神经型α疱疹病毒，包括单纯疱疹1型（HSV-1），转录一个潜伏期相关转录本（LAT）。HSV-1 LAT促进病毒再激活，其启动子包被含有翻译后修饰的组蛋白，可增强转录（常染色质）。其他HSV-1基因的启动子与抑制转录的修饰组蛋白（异染色质）结合。维持组蛋白修饰的机制尚不清楚，但可能涉及染色质绝缘体对组蛋白复合物的物理分离。总的来说，HSV-1 LAT促进潜伏病毒DNA再激活的能力为我的假设提供了理论依据，即潜伏感染的人类神经节中转录的一个或多个VZV基因通过对组蛋白修饰的影响促进潜伏VZV的再激活。两个具体目标将检验我们的假设。目的1将确定潜伏期表达的VZV基因启动子上组蛋白的翻译后修饰。目的2将研究常染色质和异染色质组蛋白修饰维持的机制。我们有独特的资格来开展我们的研究，因为我们有在尸检中获得的新鲜人类神经节的持续供应，几十年的专业知识研究潜伏性和裂解性VZV转录组，并开发了ChIP检测和基于pcr的多重检测来分析潜伏性VZV感染的人类神经节。有了对VZV基因的表观遗传调控的理解，我们将能够设计治疗药物来对抗病毒再激活，减轻老年人严重的神经系统疾病。

DESCRIPTION (provided by applicant): Varicella zoster virus (VZV), a ubiquitous neurotropic alphaherpesvirus that causes varicella (chickenpox), becomes latent in cranial nerve ganglia, dorsal root ganglia and autonomic ganglia along the entire neuraxis. VZV reactivation, mostly in elderly and immunocompromised individuals, causes zoster, often followed by postherpetic neuralgia, myelitis, meningoencephalitis, vasculopathy and ocular diseases. No other human herpesvirus causes such a wide spectrum of disease. Although zoster vaccine reduces the incidence of zoster by 51.3% within 3 years after immunization, nearly 400,000 Americans still develop zoster every year, of which about 200,000 experience PHN; others develop stroke, paralysis and blindness. None of these neurological disorders would occur if virus reactivation could be prevented. Although the molecular mechanism(s) of VZV reactivation is unknown, VZV is unique in that no less than 12 VZV transcripts are detected in latently infected human ganglia, whereas all other neurotropic alphaherpesviruses, including herpes simplex-1 (HSV-1), transcribe a single latency associated transcript (LAT). HSV-1 LAT facilitates virus reactivation, and its promoter is coated with histones containing post-translational modifications that enhance transcription (euchromatin). Promoters for other HSV-1 genes are bound by modified histones that repress transcription (heterochromatin). The mechanism by which histone modifications are maintained is unknown, but may involve physical separation of histone complexes by chromatin insulators. Overall, the ability of the HSV-1 LAT to facilitate reactivation of latent virus DNA provides a rationale for my hypothesis that one or more VZV genes transcribed in latently infected human ganglia facilitate reactivation of latent VZV through their effects on histone modification. Two specific aims will test our hypothesis. Aim 1 will identify post- translational modifications of histones on promoters of VZV genes expressed during latency. Aim 2 will investigate the mechanism by which euchromatic and heterochromatic histone modification are maintained. We are uniquely qualified to conduct our proposed studies since we have a continuous supply of fresh human ganglia obtained at autopsy, decades of expertise studying both the latent and lytic VZV transcriptome, and have developed ChIP assays and PCR-based multiplex assays to analyze human ganglia latently infected with VZV. Armed with an understanding of the epigenetic regulation of VZV genes, we will be able to design therapeutic agents to combat virus reactivation and mitigate sever neurologic disease in the elderly.