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

单纯疱疹病毒1型和2型（hsv - 1,2）是重要的人类病原体，例如，可引起播散性和危及生命的新生儿感染和脑炎。在美国，它们也是角膜移植最常见的感染性原因。生殖器疱疹感染也是艾滋病毒传播的主要危险因素。急性疱疹感染在几天内就会消退，但病毒随后会在周围神经系统神经元中以潜伏状态持续一生。潜伏病毒周期性地重新激活，使疾病复发。虽然没有可用的疫苗，但自1963年以来，针对单纯疱疹病毒的特异性抗病毒药物已在临床上使用。尽管如此，这些病毒在潜伏感染中持续存在的能力，在潜伏感染中它们不表达可以被抗病毒药物或免疫反应靶向的蛋白质，迄今为止阻碍了治疗疗法或有效预防的发展。因此，潜伏期对1型单纯疱疹病毒的病理学和生物学至关重要，并对开发治疗方法和有效预防措施构成重大挑战。大多数目前的模型提出，表观遗传调控在溶解性和潜伏性疱疹感染中起主要作用。我们最近发现了HSV-1转录的一个新水平的表观遗传调控，转录能力的调控。染色质动力学决定了HSV-1基因组是否具有转录能力，而单个基因的表达随后在转录能力基因组中受到启动子特异性因子的调节。现在，我们将在这些研究的基础上，测试一个综合假设，即决定HSV-1转录能力的染色质动力学源于病毒基因组定位到富含染色质修饰剂、蛋白质和翻译后修饰的核结构域，这些核结构域有利于高度动态和转录活性的染色质。我们提出，正是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沉默，而它们的新形成启动了再激活过程。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一个最关键的方面。我们将使用最合适的当前技术来解决一个主要的知识缺口，表观遗传学和核结构在疱疹病毒潜伏期的建立、维持和再激活的调节中的综合作用。

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.