Prevention of VZV Reactivation

预防 VZV 重新激活

• 批准号: 8476910
• 负责人: RANDALL J. COHRS
• 金额: $ 33.75万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-15 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8476910
• 关键词: Acquired Immunodeficiency Syndrome; Age; American; Antibodies; Autonomic ganglion; Autopsy; Binding; Binding Proteins; Biological Assay; Blindness; Bovine Herpesvirus 2; Cellular Immunity; Chickenpox; Chickenpox Vaccine; Childhood; Chromatin; Complex; Cranial Nerves; DNA; DNA Sequence; DNA-Binding Proteins; Diagnosis; Disease; Elderly; Epigenetic Process; Equilibrium; Equus caballus; Euchromatin; Event; Exanthema; Ganglia; Gene Expression Profile; Genes; Genetic Transcription; Genome; Health; Herpes Simplex Infections; Herpes zoster disease; Herpesviridae; Herpesvirus 1; Herpesvirus Type 3; Heterochromatin; Histones; Human; Immunization; Immunocompromised Host; Immunosuppression; Incidence; Incontinence; Individual; Latent Virus; Life; Location; Lytic; Malignant Neoplasms; Meningoencephalitis; Modification; Molecular; Mus; Myelitis; Neuralgia; Neuraxis; Neurologic; Organ Transplantation; Pain; Paralysed; Patients; Post-Translational Protein Processing; Postherpetic neuralgia; Prevention; Proteins; Qualifying; Regulation; Rest; Retinitis; Spinal Ganglia; Stroke; Structure; Suid Herpesvirus 1; Testing; Therapeutic Agents; Transcript; Transcriptional Regulation; Transplant Recipients; Vaccines; Vascular Diseases; Viral Genes; Virus; Virus Diseases; Virus Latency; arm; base; chromatin immunoprecipitation; chronic pain; combat; design; experience; histone modification; latency associated transcript; mutant; nervous system disorder; neurotropic; physical separation; prevent; promoter; protein complex; public health relevance; viral DNA

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.

描述（由申请方提供）：水痘带状疱疹病毒（VZV）是一种普遍存在的嗜神经性α疱疹病毒，可引起水痘（水痘），潜伏于脑神经节、背根神经节和自主神经节沿着整个神经轴。VZV再激活，主要发生在老年人和免疫功能低下的个体，引起带状疱疹，通常随后出现带状疱疹后神经痛、肌痛、脑膜脑炎、血管病变和眼部疾病。没有其他人类疱疹病毒引起如此广泛的疾病。尽管带状疱疹疫苗在免疫后3年内将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PHN;其他人则发生中风、瘫痪和失明。如果可以预防病毒再激活，这些神经系统疾病都不会发生。尽管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神经节中检测到不少于12种VZV转录物，而所有其他嗜神经性α疱疹病毒，包括单纯疱疹-1（HSV-1），转录单个潜伏相关转录物（LAT）。HSV-1 LAT促进病毒再活化，其启动子被含有增强转录的翻译后修饰的组蛋白（常染色质）包被。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再活化的能力为我的假设提供了理论基础，即在潜伏感染的人神经节中转录的一个或多个VZV基因通过其对组蛋白修饰的作用促进潜伏VZV的再活化。两个具体目标将检验我们的假设。目的1鉴定VZV潜伏期基因启动子上组蛋白的翻译后修饰.目的二是研究组蛋白常染色质和异染色质修饰的维持机制。我们是唯一有资格进行我们提出的研究，因为我们有一个新鲜的人类神经节在尸检中获得的连续供应，几十年的专业知识研究潜伏和裂解VZV转录组，并已开发ChIP检测和基于PCR的多重检测来分析人类神经节潜伏感染VZV。了解了VZV基因的表观遗传调控，我们将能够设计治疗药物来对抗病毒的再激活，减轻老年人的严重神经系统疾病。