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）：进行性多灶性白质脑病 (PML) 是一种致命的脑部脱髓鞘疾病，由少突胶质细胞（中枢神经系统的髓鞘生成细胞）被人类嗜神经性多瘤病毒 JC 病毒 (JCV) 溶解性感染引起。 。 JCV 在儿童时期感染大多数人，然后保持持续但休眠的状态（称为潜伏期），此时 JCV 复制水平仍然较低。然而，在严重免疫抑制的情况下，尤其是艾滋病，JCV 在大脑中重新激活，其复制导致 PML。大脑中 JCV 重新激活和 PML 起始的机制尚不清楚，但被认为涉及免疫抑制对 TNF-1 等细胞因子的影响，或 HIV-1 通过其反式激活因子 Tat 的直接影响。我们的初步数据表明控制区域内的特定位点 (kB) 参与结合 NF-kB 以刺激转录，从而刺激 JCV 基因组的复制。该位点还结合 C/EBP2 同工型以抑制转录。我们的假设是，JCV 潜伏期和 PML 重新激活的平衡受到 NF-:B 和 C/EBP2 转录因子的调节，这两种转录因子均受到细胞因子的调节，而这些细胞因子的水平在 HIV-1 感染过程中失调。我们建议对这些细胞因子和转录因子在确定 JCV 潜伏期和重新激活以启动 PML 的平衡中的作用进行全面的实验分析。将分析细胞因子刺激、NF-kB 和 C/EBP2 对 JCV 转录、复制和生命周期的作用。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 的作用，因为 Tat 是 JCV 的有效反式激活因子，可以激活 NF-kB 信号传导并与 C/EBP2 结合。这些发现的病理学重要性将使用 PML 临床样本和对照进行评估。通过这些研究，我们希望更好地了解 JCV 潜伏期和再激活导致 PML 的分子机制，这可能为该疾病开辟新的治疗途径。公共卫生相关性 进行性多灶性白质脑病是一种致命的退行性脑部疾病，由一种称为 JCV 的病毒引起，当免疫系统受损时，该病毒就会失控。大约 5% 的艾滋病毒/艾滋病患者患有这种疾病。该提案的目的是找出导致病毒在这些患者体内生长的原因，以便我们能够开发治疗方法。