Cytokine regulation of JC virus latency and reactivation

JC病毒潜伏期和再激活的细胞因子调节

基本信息

批准号：
8703590
负责人：
MARTYN K WHITE
金额：
$ 35.1万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8703590
关键词：
AIDS/HIV problem Acetylation Acetyltransferase Acquired Immunodeficiency Syndrome Area Astrocytes Beginning of Life Binding Biological Assay Brain CCAAT-Enhancer-Binding Proteins Calcineurin Calcium Signaling Cell Line Cells Central Nervous System Diseases Childhood Chromatin Clinical DNA biosynthesis Demyelinating Diseases Demyelinations Development Disease EP300 gene Elements Epigenetic Process Event Gene Expression Genetic Transcription Goals HIV-1 Histone Deacetylase Inhibitor Histones Human Immune system Immunosuppression Incidence Indium Infection Interleukin-1 JC Virus Lesion Life Life Cycle Stages Lytic Phase Mediating Messenger RNA Molecular Monitor Mutation Analysis Myelin NF-kappa B Neuroglia Nuclear Inclusion Oligodendroglia Patients Persons Population Process Progressive Multifocal Leukoencephalopathy Protein Acetylation Regulation Reporter Risk Role Sampling Signal Transduction Site Site-Directed Mutagenesis Stem cells System TNF gene TNFRSF1A gene Time Transcription Coactivator Viral Viral Proteins Virus Virus Diseases Virus Latency Work activating transcription factor antiretroviral therapy cytokine experimental analysis extracellular fetal interest mutant neurotropic novel novel therapeutics oligodendroglioma p65 promoter protein expression public health relevance reactivation from latency receptor research study response transcription factor viral DNA

项目摘要

DESCRIPTION (provided by applicant): The fatal CNS demyelinating disease progressive multifocal leukoencephalopathy (PML) is caused by the productive infection of glial cells with the human neurotropic polyomavirus, JC (JCV). JCV infects most people early in life and then remains in a latent state where JCV gene expression and replication cannot be detected. However, in the context of severe immunosuppression, especially HIV-1/AIDS, JCV becomes reactivated leadings to PML. In regard to reactivation, our working hypothesis is that JCV gene expression is switched on in glial cells of the brain by the action of proinflammatory cytokines. This application is a competitive renewal of our R01 entitled "Cytokine Regulation of JC Virus Latency and Reactivation", in which we have pursued this hypothesis. We have observed that transcription from both the early and late JCV promoters is positively regulated by NF-?B and negatively regulated by C/EBP¿, which act at a common element (KB) in the JCV control region. The activities of both of these transcription factors are modulated by extracellular cytokines and both JCV promoters are activated by cytokines, e.g., TNF-? and IL-1? through the KB element. TNF-? and its receptor were found to be abundant in clinical samples of HIV-1/PML lesions. In these studies, we also made two novel and interesting observations. Firstly, we found that a third transcription factor NFAT4, which is activated by cytokines and calcium signaling via calcineurin, can bind and stimulate the JCV KB element in cooperation with NF-?B and is also negatively regulated by C/EBP?. Secondly, epigenetic events involving protein acetylation are involved in this process, since histone deacetylase inhibitors potently stimulate JCV early and late transcription and mutation analysis has implicated the KB element in this effect. In the light of our new findings, we have now extended our hypothesis and propose that, in addition to NF-?B and C/EBP?, the transcription factor NFAT4 and epigenetic control by protein acetylation are also involved in viral reactivation. We now propose a comprehensive experimental analysis of the roles of these factors in determining JCV latency/reactivation and its response to the status of extracellular cytokines. Through these studies, we hope to gain a better understanding of the molecular mechanisms involved in JCV latency and reactivation to cause PML and this may open new therapeutic avenues to this disease.

描述（由适用提供）：致命的中枢神经系统脱髓鞘性疾病进行性多灶性白细胞病变（PML）是由人神经性多瘤病毒（JC）的神经胶质细胞产物感染引起的。 JCV感染大多数人生早期的人，然后一直处于无法检测到JCV基因表达和复制的潜在状态。但是，在严重的免疫抑制（尤其是HIV-1/AIDS）的背景下，JCV重新激活了对PML的铅。关于重新激活，我们的工作假设是JCV基因表达通过促炎细胞因子的作用在大脑的神经胶质细胞中打开。该应用是对我们的R01的竞争更新，标题为“ JC病毒潜伏期和重新激活的细胞因子调节”，其中我们提出了这一假设。我们已经观察到，来自JCV早期和晚期启动子的转录受NF- b的正调控，并受到C/EBP的负面调节，C/eBp¿的转录对JCV控制区域的共同元素（Kb）作用。这两个转录因子的活性均由细胞外细胞因子调节，并且两个JCV启动子都被细胞因子激活，例如TNF-？和IL-1？通过KB元素。 tnf-？发现其受体在HIV-1/PML病变的临床样本中很丰富。在这些研究中，我们还做出了两个新颖有趣的观察结果。首先，我们发现第三个转录因子NFAT4被钙调神经酶通过细胞因子和钙信号传导激活，可以与NF-？b合作结合和刺激JCV KB元素，并且也会受C/EBP的负调节。其次，涉及蛋白乙酰化的表观遗传事件参与了此过程，因为组蛋白脱乙酰基酶抑制剂潜在地刺激JCV早期和晚期转录和突变分析在这种作用中实施了KB元素。鉴于我们的新发现，我们现在扩展了我们的假设和建议，即除Nf- b和c/c/eBP外，转录因子NFAT4 NFAT4和蛋白质乙酰化的表观遗传控制也参与了病毒重新激活。现在，我们对这些因素在确定JCV潜伏期/重新激活及其对细胞外细胞因子状态的反应中的作用进行了全面的实验分析。通过这些研究，我们希望更好地了解JCV潜伏期和重新激活的分子机制，以引起PML，这可能为该疾病打开新的治疗途径。