Transcriptional control of herpes simplex virus lytic infection and latency-reactivation cycles

单纯疱疹病毒溶解感染和潜伏-再激活周期的转录控制

基本信息

批准号：
10692043
负责人：
THOMAS M KRISTIE
金额：
$ 119.8万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10692043
关键词：
Address Afferent Neurons Animal Model Biochemical Biological Models Cell Communication Cell Culture System Cell Culture Techniques Chromatin Complex DNA Binding Data Disease Early Gene Transcriptions Enhancers Epigenetic Process Gene Expression Genes Genetic Transcription Genital Genitalia Goals Histones Immediate-Early Genes Individual Lesion Life Cycle Stages Lytic Lytic Phase Mediating Multiprotein Complexes Neurons Oral Play Primary Cell Cultures Primary Infection Proteins Recurrence Role Signal Transduction Simplexvirus Stimulus Transcription Coactivator Transcriptional Elongation Factors Transcriptional Regulation Viral Viral Genes Viral Genome Virus Virus Activation Virus Assembly Virus Latency chromatin modification design histone methyltransferase host cell factor C1 in vivo insight latent infection nucleocytoplasmic transport protein complex reactivation from latency

项目摘要

Once an individual is infected with herpes simplex virus (HSV), the virus establishes a latent infection in sensory neurons. Periodically, stimuli induce lytic reactivation that results in disease ranging from recurrent oral or genital lesions to severe ocular disease. Initiation of lytic infection as well as reactivation from latency depends upon the expression of the viral (IE) immediate early genes. These genes are controlled by complex multiprotein enhancer assemblies that consists of viral and cellular components. Studies are designed to identify critical components and investigate their interactions and their biochemical functions in order to provide insights into the mechanisms that mediate viral IE gene expression. The mammalian transcriptional coactivator HCF-1 is one of the essential factors involved in both the assembly of the viral IE enhancer complex and the activation of IE gene transcription. Studies address functions of this coactivator during the viral lytic cycle and elucidate complex viral-cell interactions that impact the lytic and latent states of the viral life cycle. Previous studies have determined that HCF-1 (i) functions as a component of chromatin modification complexes that are essential for modulating the chromatin status of the viral IE genes upon initiation of lytic infection; (ii) interacts with transcriptional elongation factors to drive productive primary infection and viral reactivation from latency; and (iii) is subject to signal mediated nuclear transport in latently infected sensory neurons that correlated with viral reactivation. These data indicate that HCF-1 and its associated protein components, play multiple critical roles in the switch from latency to the initiation of reactivation. In fiscal year 2022, using two distinct approaches, specific depletion of HCF-1 in sensory neurons in vivo demonstrated that HCF-1 is required to promote viral reactivation, in part, by modulating the epigenetic state of the latent viral genome. In separate studies, (i) a histone methyltransferase was implicated in induction of viral IE gene expression and inhibition of this factor suppressed initiation of lytic infection and productive reactivation from latency; and (ii) an HCF-1 associated epigenetic complex was shown to be required to reduce specific repressive histone marks to promote viral gene expression in primary cell cultures and in a neuronal cell culture system.

一旦一个人感染了单纯疱疹病毒（HSV），该病毒就会在感觉神经元中产生潜在的感染。周期性地，刺激会引起裂解再活化，从而导致疾病从复发性口服或生殖器病变到严重的眼部疾病。裂解感染的开始以及潜伏期的重新激活取决于病毒（即）直接早期基因的表达。这些基因由由病毒和细胞成分组成的复杂多蛋白增强子组件控制。研究旨在识别关键成分并研究其相互作用及其生化功能，以便深入了解介导病毒IE基因表达的机制。哺乳动物的转录共激活因子HCF-1是病毒IE增强子复合物和IE基因转录激活的基本因素之一。研究解决了该在病毒裂解周期期间该共激活因子的功能，并阐明了影响病毒生命周期的裂解状态和潜在状态的复杂病毒细胞相互作用。先前的研究已经确定，HCF-1（i）是染色质修饰复合物的组成部分，这对于在开始裂解感染后调节病毒IE基因的染色质状态至关重要。（ii）与转录伸长因子相互作用，以驱动潜伏期的生产性原发性感染和病毒重新激活；（iii）在与病毒重新激活相关的潜在感染感觉神经元中受信号介导的核转运。这些数据表明，HCF-1及其相关的蛋白质成分在从潜伏期转变为重新激活的转换中起多个关键作用。在2022财政年度，使用两种不同的方法，体内感觉神经元中HCF-1的特异性耗竭表明，HCF-1是通过调节潜在病毒基因组的表观遗传状态来促进病毒重新激活的。在单独的研究中，（i）组蛋白甲基转移酶与诱导病毒IE基因表达的诱导以及对该因子的抑制抑制了裂解感染的起始和潜伏期的生产性重新激活；（ii）显示出HCF-1相关的表观遗传复合物被证明是为了减少特定的抑制性组蛋白标记，以促进原代细胞培养物和神经元细胞培养系统中的病毒基因表达。