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

• 批准号: 7760121
• 负责人: MARTYN K WHITE
• 金额: $ 37.13万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7760121
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Adenovirus Vector; Adenoviruses; Astrocytes; Bacteria; Binding; Binding Sites; Biological Assay; Brain; Brain Diseases; Carbon; Cell Line; Cell Nucleus; Cells; Childhood; Chronic; Clinical; Critiques; Cytokine Signaling; Cytoplasm; Data; Demyelinating Diseases; Development; Disease; Ectopic Expression; Equilibrium; Figs - dietary; FuGene; Gene Expression; Genes; Genetic Transcription; Genome; Green Fluorescent Proteins; HIV-1; Human; Immune system; Immunosuppression; Infection; Inflammatory; Interleukin-6; JC Virus; Length; Life Cycle Stages; Lip structure; Lipids; Lytic Phase; Manufacturer Name; Messenger RNA; Molecular; Monitor; Mutation; Myelin; NF-kappa B; National Coalition for Cancer Research; Nucleic Acid Regulatory Sequences; Oligodendroglia; Patients; Phospho-Specific Antibodies; Phosphorylation; Phosphorylation Site; Plasmids; Polyomavirus; Population; Prevalence; Principal Investigator; Progressive Multifocal Leukoencephalopathy; Protein Isoforms; Protocols documentation; Reagent; Regulation; Relative (related person); Reporter; Research Design; Role; Running; Sampling; Signal Pathway; Signal Transduction; Site; Time; Toxic effect; Trans-Activators; Transfection; Up-Regulation; Viral; Viral Proteins; Virus; Virus Diseases; Virus Latency; Virus Replication; base; cytokine; experimental analysis; factor C; fetal; mutant; neurotropic; novel therapeutics; oligodendroglioma; oligofectamine; programs; promoter; protein expression; public health relevance; research study; response; transcription factor; viral DNA

DESCRIPTION (provided by applicant): Progressive Multifocal Leukoencephalopathy (PML) is a fatal demyelinating disease of the brain and is caused by lytic infection of oligodendrocytes, the myelin-producing cells of the CNS, with the human neurotropic polyomavirus, JC virus (JCV). JCV infects most people in childhood and then remains in a persistent but dormant state known as latency where the level of JCV replication remains low. However, in the context of severe immunosuppression, especially AIDS, JCV becomes reactivated in the brain where its replication leads to PML. The mechanisms involved in the reactivation of JCV in the brain and the initiation of PML are unknown but are thought to involve effects of immunosuppression on cytokines such as TNF-1, or direct effects of HIV-1 via its transactivator, Tat. Our preliminary data point to the involvement of a specific site (kB) within the control region that binds NF-kB to stimulate transcription and hence replication of the JCV genome. This site also binds C/EBP2 isoforms to inhibit transcription. Our hypothesis is that the balance of JCV latency and reactivation to PML is regulated by the NF-:B and C/EBP2 transcription factors, which are both regulated by cytokines whose levels are dysregulated during the course of HIV-1 infection. We propose a comprehensive experimental analysis of the roles of these cytokines and transcription factors in determining the balance of JCV latency and reactivation to initiate PML. The role of cytokine stimulation, NF-kB and C/EBP2 on JCV transcription, replication and life cycle will be analyzed. Mutant forms of the kB promoter element and C/EBP2 mutants will be analyzed to investigate the molecular mechanisms involved. We will also investigate the effect of HIV-1 Tat, since Tat is a potent transactivator of JCV that can activate NF-kB signaling and also binds to C/EBP2. The pathological importance of these findings will be assessed using PML clinical samples and controls. 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. PUBLIC HEALTH RELEVANCE Progressive Multifocal Leukoencephalopathy is a fatal degenerative brain disease that is caused by a virus called JCV that runs out of control when the immune system is damaged. This disease afflicts about 5% of people with HIV/AIDS. The aim of this proposal is to find out what makes the virus grow in these patients so that we can develop treatments.

描述（由申请人提供）：进行性多灶性白细胞病原（PML）是一种致命的大脑脱髓疾病，是由少突胶质细胞的裂解感染引起的，CNS的髓磷脂产生细胞，具有人类神经局部多头性疾病，具有人类神经毒性多头病毒（JC Virus）。 JCV感染了童年时期的大多数人，然后仍然处于一种持久但处于休眠状态，称为潜伏期，其中JCV复制水平仍然很低。但是，在严重的免疫抑制，尤其是艾滋病的背景下，JCV在大脑中复制在其复制导致PML的情况下重新激活。 JCV在大脑和PML的引发中涉及的机制尚不清楚，但被认为涉及免疫抑制对细胞因子（例如TNF-1）的影响，或通过其反式激活剂TAT对HIV-1的直接影响。我们的初步数据表明，特定位点（KB）在控制区域内结合NF-KB以刺激转录并因此复制JCV基因组。该位点还结合C/EBP2同工型抑制转录。我们的假设是，JCV潜伏期和对PML的重新激活的平衡受NF-：B和C/C/EBP2转录因子的调节，这两者都受HIV-1感染过程中水平失调的细胞因子调节。我们对这些细胞因子的作用以及转录因子在确定JCV潜伏期和重新激活以启动PML方面的作用进行了全面的实验分析。细胞因子刺激，NF-KB和C/EBP2在JCV转录，复制和生命周期中的作用将进行分析。将分析KB启动子元件和C/EBP2突变体的突变形式，以研究所涉及的分子机制。我们还将研究HIV-1 TAT的效果，因为TAT是JCV的有效反式激活器，可以激活NF-KB信号传导并与C/EBP2结合。这些发现的病理重要性将使用PML临床样本和对照组进行评估。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。公共卫生相关性渐进性多灶性白细胞病是一种致命的退化性脑疾病，是由一种称为JCV的病毒引起的，当免疫系统受损时，它无法控制。这种疾病困扰着大约5％的艾滋病毒/艾滋病患者。该建议的目的是找出使这些患者中病毒生长的原因，以便我们可以发展治疗。