Proteins Mediating Interaction of HIV-1 and JCV in CNS

介导中枢神经系统中 HIV-1 和 JCV 相互作用的蛋白质

• 批准号: 7991800
• 负责人: EDWARD M. JOHNSON
• 金额: $ 41.5万
• 依托单位: EASTERN VIRGINIA MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-02-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7991800
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Automobile Driving; Binding; Biological Assay; Brain; Categories; Cells; Conditioned Culture Media; DNA biosynthesis; Data; Development; Environment; Exposure to; Gene Chips; Genes; Genetic Transcription; Goals; HIV; HIV-1; Immunohistochemistry; Immunologic Deficiency Syndromes; Immunomodulators; Immunosuppression; Incidence; Individual; Infection; Intervention; JC Virus; Knock-out; LacZ Genes; Late Gene Transcriptions; Lesion; Mediating; Mediation; Methods; Microglia; Mus; Neurodegenerative Disorders; Neuroglia; Nuclear; Oligodendroglia; Pathway interactions; Patients; Plasmids; Play; Procedures; Process; Production; Progressive Multifocal Leukoencephalopathy; Proteins; PurA protein; Regulatory Pathway; Reporter Genes; Research Personnel; Role; Signal Pathway; Signal Transduction; Smad Proteins; Smad protein; T-Lymphocyte; Testing; Tissues; Transgenic Mice; Virus Activation; Virus Diseases; brain tissue; chromatin immunoprecipitation; cyclin T1; cytokine; in vivo; macrophage; monocyte; mouse model; programs; promoter; research study; tat Protein; viral DNA

DESCRIPTION (provided by applicant): The overall goal of this project is to elucidate the mechanisms by which activation of JC virus in glial cells of the brain is influenced by HIV-1 infection. JC virus (JCV) is the etiologic agent of the neurodegenerative disease, progressive multifocal leukoencephalopathy (PML). JCV is normally latent in non-immunocompromised people, but it is activated in brains of individuals with AIDS. Because of the high incidence of PML in AIDS, we have hypothesized that HIV-1 plays a role greater than that expected of immunosuppression alone. We shall capitalize upon our extensive results of the last few years, which can be grouped in two categories. In one we have demonstrated the role of the Tat protein of HIV-1 in stimulating JCV late gene transcription and JCV DMA replication. In the other we have demonstrated that HIV-1 infection alters pathways of production and signal transduction of immunomodulators, including TGF-01, in the CNS. We propose to determine how the Smad nuclear effectors of TGF-31 interact with Tat and its cellular partner proteins Pura and Cyclin T1/ Cdk9 at JCV and PCNA promoter sequences. Our new double chromatin immunoprecipitation method will be employed in conjunction with functional studies on JCV DMA replication and gene transcription. We shall employ a microarray to identify genes in glial cells regulated by exposure to cytokines produced by HIV-1-infected cells. We shall employ a transgenic mouse model to test the hypothesis that factors produced by HIV-1-infected cells can influence JCV promoters in the CNS and play a role in early steps of PML development. Tissue from the Manhattan HIV Brain Bank will be used to determine whether TGF-P1 or its nuclear effectors, Smad3, Smad4 or Fasti, are localized or activated in specific cells of PML lesions. Results will help elucidate pathways of activation of JCV in the brain and will help target particular molecular interactions for therapy.

描述(申请人提供)：这个项目的总体目标是阐明HIV-1感染影响JC病毒在大脑神经胶质细胞中激活的机制。JC病毒是一种神经退行性疾病--进行性多灶性白质脑病(PML)的病原体。JCV在非免疫功能低下的人中通常是潜伏的，但在艾滋病患者的大脑中会被激活。由于PML在艾滋病中的高发病率，我们假设HIV-1发挥的作用比免疫抑制单独发挥的作用更大。我们将利用我们过去几年取得的广泛成果，这些成果可分为两类。在一项研究中，我们展示了HIV-1的Tat蛋白在刺激JCV晚期基因转录和JCV DMA复制中的作用。在另一方面，我们已经证明了HIV-1感染改变了中枢神经系统中免疫调节剂的产生和信号转导的途径，包括转化生长因子-01。我们建议确定转化生长因子-31的Smad核效应因子如何与TAT及其细胞伙伴蛋白Pura和Cyclin T1/CDK9在JCV和PCNA启动子序列上相互作用。我们新的双染色质免疫沉淀方法将与JCV DMA复制和基因转录的功能研究相结合。我们将使用微阵列来识别神经胶质细胞中的基因，这些基因受到HIV-1感染细胞产生的细胞因子的影响。我们将使用转基因小鼠模型来检验这一假设，即HIV-1感染细胞产生的因素可以影响中枢神经系统中的JCV启动子，并在PML发展的早期阶段发挥作用。曼哈顿艾滋病毒脑库的组织将用于确定转化生长因子-P1或其核效应因子Smad3、Smad4或Fasti是否在PML病变的特定细胞中定位或激活。结果将有助于阐明JCV在大脑中的激活途径，并将有助于针对特定的分子相互作用进行治疗。

项目成果

SMAD proteins of oligodendroglial cells regulate transcription of JC virus early and late genes coordinately with the Tat protein of human immunodeficiency virus type 1.

少突胶质细胞的 SMAD 蛋白与人类免疫缺陷病毒 1 型的 Tat 蛋白协调调节 JC 病毒早期和晚期基因的转录。

• DOI: 10.1099/vir.0.011072-0
• 发表时间: 2009
• 期刊: The Journal of general virology
• 作者: Stettner,MichelleR;Nance,JonasA;Wright,ClaytonA;Kinoshita,Yayoi;Kim,Woong-Ki;Morgello,Susan;Rappaport,Jay;Khalili,Kamel;Gordon,Jennifer;Johnson,EdwardM
• 通讯作者: Johnson,EdwardM

Role of Puralpha in the modulation of homologous recombination-directed DNA repair by HIV-1 Tat.

Puralpha 在 HIV-1 Tat 调节同源重组定向 DNA 修复中的作用。

• 发表时间: 2008
• 期刊: Anticancer research
• 影响因子: 2
• 作者: Wang,Huichen;White,MartynK;Kaminski,Rafal;Darbinian,Nune;Amini,Shohreh;Johnson,EdwardM;Khalili,Kamel;Rappaport,Jay
• 通讯作者: Rappaport,Jay

Effects of Tat proteins and Tat mutants of different human immunodeficiency virus type 1 clades on glial JC virus early and late gene transcription.

1型人类免疫缺陷病毒不同进化枝的Tat蛋白和Tat突变体对胶质JC病毒早期和晚期基因转录的影响。

• DOI: 10.1099/vir.0.047902-0
• 发表时间: 2013
• 期刊: The Journal of general virology
• 作者: Wright,ClaytonA;Nance,JonasA;Johnson,EdwardM
• 通讯作者: Johnson,EdwardM

PURA, the gene encoding Pur-alpha, member of an ancient nucleic acid-binding protein family with mammalian neurological functions.

• DOI: 10.1016/j.gene.2017.12.004
• 发表时间: 2018-02-15
• 期刊: Gene
• 影响因子: 3.5
• 作者: Daniel DC;Johnson EM
• 通讯作者: Johnson EM

JCV agnoprotein-induced reduction in CXCL5/LIX secretion by oligodendrocytes is associated with activation of apoptotic signaling in neurons.

• DOI: 10.1002/jcp.23065
• 发表时间: 2012-08
• 期刊: JOURNAL OF CELLULAR PHYSIOLOGY
• 影响因子: 5.6
• 作者: Merabova, Nana;Kaminski, Rafal;Krynska, Barbara;Amini, Shohreh;Khalili, Kamel;Darbinyan, Armine
• 通讯作者: Darbinyan, Armine