Chromatin dynamics in the regulation of herpes simplex virus 1 gene expression.

单纯疱疹病毒 1 基因表达调节中的染色质动力学。

• 批准号: 10613368
• 负责人: Luis M. Schang
• 金额: $ 37.28万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-11 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10613368
• 关键词: Acute; Acyclovir; Address; Antiviral Agents; Architecture; Back; Binding; Biology; Cell Nucleus; Cells; Chromatin; Chromatin Remodeling Factor; Clinical; Competence; Complex; Development; Disease; Encephalitis; Environment; Epidemiology; Epigenetic Process; Eye Infections; FDA approved; Gene Expression; Genes; Genetic Transcription; Genome; HIV; HIV Infections; Herpes Simplex Infections; Herpes encephalitis; Herpesviridae; Herpesviridae Infections; Herpesvirus 1; Histones; Human Herpesvirus 2; Immune response; Individual; Keratoplasty; Knowledge; Life; Location; Lytic; Lytic Phase; Maintenance; Maps; Medical; Modeling; Modification; Neuroglia; Neurologic; Neurons; Nuclear; Nucleosome Core Particle; Pathogenesis; Pathology; Peripheral Nervous System; Play; Post-Translational Protein Processing; Preventive vaccine; Process; Property; Prophylactic treatment; Proteins; Publishing; Recrudescences; Regulation; Rest; Risk; Risk Factors; Role; SWI/SNF Family Complex; Secure; Simplexvirus; Stress; Technology; Testing; Therapeutic; Trans-Activators; Transcription Coactivator; Transcriptional Regulation; VP 16; Variant; Viral; Viral Genome; Virus; Virus Latency; Work; Zika Virus; chromatin protein; curative treatments; epigenetic regulation; experimental study; genital herpes; human pathogen; human pluripotent stem cell; latent infection; neonatal infection; nerve stem cell; novel; permissiveness; promoter; reactivation from latency; recruit; therapeutic vaccine; transmission process; vaccine access; Acute; Acyclovir; Address; Antiviral Agents; Architecture; Back; Binding; Biology; Cell Nucleus; Cells; Chromatin; Chromatin Remodeling Factor; Clinical; Competence; Complex; Development; Disease; Encephalitis; Environment; Epidemiology; Epigenetic Process; Eye Infections; FDA approved; Gene Expression; Genes; Genetic Transcription; Genome; HIV; HIV Infections; Herpes Simplex Infections; Herpes encephalitis; Herpesviridae; Herpesviridae Infections; Herpesvirus 1; Histones; Human Herpesvirus 2; Immune response; Individual; Keratoplasty; Knowledge; Life; Location; Lytic; Lytic Phase; Maintenance; Maps; Medical; Modeling; Modification; Neuroglia; Neurologic; Neurons; Nuclear; Nucleosome Core Particle; Pathogenesis; Pathology; Peripheral Nervous System; Play; Post-Translational Protein Processing; Preventive vaccine; Process; Property; Prophylactic treatment; Proteins; Publishing; Recrudescences; Regulation; Rest; Risk; Risk Factors; Role; SWI/SNF Family Complex; Secure; Simplexvirus; Stress; Technology; Testing; Therapeutic; Trans-Activators; Transcription Coactivator; Transcriptional Regulation; VP 16; Variant; Viral; Viral Genome; Virus; Virus Latency; Work; Zika Virus; chromatin protein; curative treatments; epigenetic regulation; experimental study; genital herpes; human pathogen; human pluripotent stem cell; latent infection; neonatal infection; nerve stem cell; novel; permissiveness; promoter; reactivation from latency; recruit; therapeutic vaccine; transmission process; vaccine access

Herpes simplex virus 1 and 2 (HSV-1, 2) are important human pathogens, producing disseminated and life- threatening neonatal infections and encephalitis, for example. They also are the most common infectious cause of corneal transplant in the USA. Genital herpes infections are a major risk factor for HIV transmission, too. Acute herpes infections resolve in a matter of days, but the virus then persists for life in a dormant, latent, state in peripheral nervous system neurons. Latent virus periodically reactivates producing recrudescence of disease. Although no vaccines are available, specific antivirals for herpes simplex virus have been clinically used since 1963. Nonetheless, the ability of these viruses to persist in latent infections, in which they express no protein that can be targeted with antivirals or immune responses, has precluded to date the development of curative therapies or effective prophylaxis. Latency is thus critical to the pathology and biology of HSV-1 and poses a major challenge to the development of curative therapeutics and effective prophylaxis. Most current models propose that epigenetic regulation plays a major role during lytic and latent herpes infection. We have recently identified a novel level of epigenetic regulation of HSV-1 transcription, regulation of transcription competency. Chromatin dynamics dictate whether HSV-1 genomes are transcriptionally competent or not, whereas the expression of individual genes is then regulated in the transcriptionally competent genomes by promoter specific factors. We will now build on those studies by testing an integrative hypothesis in which the chromatin dynamics that dictate HSV-1 transcriptional competence result from the localization of the viral genomes into nuclear domains enriched in chromatin modifiers, proteins, and posttranslational modifications that favor a highly dynamic, and transcriptionally active, chromatin. We propose that it is the destruction (or lack of assembly) of these domains in neurons what favors the silencing of the viral genomes required for latency, and their neo-formation what starts the process of reactivation. Our studies are thus centered on one of the most critical aspects of herpes simplex virus biology, pathology and epidemiology. We will use the most appropriate current technologies to address a major knowledge gap, the combined roles of epigenetics and nuclear architecture in the regulation of the establishment, maintenance and reactivation of herpes virus latency.

例如，单纯疱疹病毒1和2（HSV-1，2）是重要的人类病原体，例如产生传播和生命威胁的新生儿感染和脑炎。它们也是美国角膜移植最常见的传染病。生殖器疱疹感染也是HIV传播的主要危险因素。急性疱疹感染在几天之内就会解决，但随后病毒在周围神经系统神经元中处于休眠，潜在状态。潜在病毒会定期重新激活疾病的复发。尽管没有疫苗可用，但自1963年以来一直在临床上使用疱疹病毒的特异性抗病毒药。尽管如此，这些病毒在潜在感染中持续存在的能力，在这种潜在感染中，它们没有表达可靶向抗病毒药或免疫反应的蛋白质，但已被排除在治愈治疗或有效的预防疗法的发展。因此，潜伏期对HSV-1的病理学和生物学至关重要，对治愈性疗法和有效预防的发展构成了重大挑战。大多数当前模型表明，表观遗传调节在裂解和潜在疱疹感染中起着重要作用。我们最近确定了HSV-1转录，转录能力调节的新型表观遗传调节水平。染色质动力学决定了HSV-1基因组是否具有转录能力，而然后通过启动子特定因素调节单个基因的表达。现在，我们将通过测试一个综合假设来建立在这些研究的基础上，在这种假设中，该假设决定了HSV-1转录能力的染色质动力学，这是由于病毒基因组的定位到富含染色质修饰剂，蛋白质和后翻译后修饰的核域中的定位而产生的，这些修饰有利于高度动态和转录活性，并且具有转录活性，染色质。我们认为，神经元中这些结构域的破坏（或缺乏组装）有利于潜伏期所需的病毒基因组的沉默及其新形态化的原因是什么开始了重新激活过程。因此，我们的研究集中在单纯疱疹病毒生物学，病理学和流行病学的最关键方面之一。我们将使用最合适的当前技术来解决主要的知识差距，表观遗传学和核结构在调节疱疹病毒潜伏期的建立，维持和重新激活中的结合作用。