BAG3 mediates interplay of HIV-1 and JCV in brain

BAG3 介导大脑中 HIV-1 和 JCV 的相互作用

• 批准号: 8464274
• 负责人: Kamel Khalili
• 金额: $ 32.79万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-02 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8464274
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Apoptosis; Apoptotic; Astrocytes; Biological; Brain; Caspase; Cell Cycle; Cell Cycle Progression; Cell Membrane Permeability; Cell Survival; Cells; Central Nervous System Diseases; Central Nervous System Infections; DNA Damage; DNA Repair; Development; Event; Gene Expression; Genes; Genetic Transcription; Genome; HIV-1; Health; Heat-Shock Proteins 70; Human; Infection; JC Virus; Mediating; Microglia; Molecular; Molecular Chaperones; Neuraxis; Neuroglia; Neuropathogenesis; Pathway interactions; Patients; Play; Production; Progressive Multifocal Leukoencephalopathy; Proteins; Regulation; Role; Sampling; Small Interfering RNA; Stress; Survival Rate; TFAP2A gene; Therapeutic Agents; Viral; Viral Regulatory Proteins; Viral Tumor Antigens; Virus; biological adaptation to stress; brain tissue; cell type; genetic regulatory protein; macrophage; mitochondrial membrane; multicatalytic endopeptidase complex; nervous system disorder; novel; pathogen; research clinical testing; response; transcription factor

DESCRIPTION (provided by applicant): HIV-1 infection of the central nervous system (CNS) induces conditions of stress that trigger an array of cellular responses with the capacity to affect HIV-1 gene expression, alter the homeostatic state of the host cell, and stimulate co-existing opportunistic pathogens. Recent results from evaluating brain tissue obtained from AIDS patients with neurologic disorders have revealed enhanced expression of BAG3 in astrocytes and perivascular microglial cells. BAG3 is an anti-apoptotic/pro-survival protein that associates with a key stress response chaperone protein, HSP70, and modulates its activity on re-folding of damaged proteins and delivery of its cargo to proteasomes. These events influence several pathways involved in cell survival and apoptosis including mitochondrial membrane depolarization, caspase activation, DNA damage, cell cycle progression, and others. Activation of BAG3 can also be observed during the course of HIV-1 infection of microglia, a cell type that supports viral replication in the brain. Interestingly, activation of BAG3 appears to augment cell survival as silencing of BAG3 by siRNA increases the rate of apoptosis in HIV-1 infected microglial cells. Induction of BAG3 may have a negative impact on HIV-1 replication as BAG3 possesses the ability to suppress HIV-1 gene transcription in both microglia and astrocytes. Indeed these events may be reversed once the level of BAG3 is reduced in the cells. In glial cells this can be accomplished upon activation of the human opportunistic virus, JCV, whose early protein suppresses BAG3 transcription and may alleviate the negative effect of BAG3 on HIV-1 and promote apoptotic pathways. These observations are relevant to the neuropathogenesis of AIDS as replication of JCV, which results in the development of progressive multifocal leukoencephalopthy (PML), is frequently seen in AIDS patients. All of these observations have led us to hypothesize that BAG3, by assisting cells to survive the initial infection with HIV-1, can play a critical role in converting cells to become a long-term reservoir for the virus. With this notion, we plan to investigate the molecular events involved in the differential regulation of BAG3 in CNS cells, identify the pathway by which BAG3 suppresses HIV-1 expression and replication, investigate the impact of JCV via suppression of BAG3 upon HIV-1 expression, and determine the mechanism involved in BAG3 mediated cell survival in HIV-1 infected cells. We will employ molecular, cellular, and virological approaches to address these questions and examine the biological relevance of our findings by immunohistochemical evaluation of clinical samples from patients with HIV-1 CNS disease.

描述（由申请人提供）：中枢神经系统（CNS）的HIV-1感染引起压力条件，触发一系列细胞反应，具有影响HIV-1基因表达的能力，改变宿主细胞的稳态状态，并刺激共存在的机会性病原体。评估从艾滋病患者获得神经系统疾病的患者获得的脑组织的最新结果显示，星形胶质细胞和血管周围小胶质细胞中BAG3的表达增强了。 BAG3是一种抗凋亡/促凋亡蛋白，它与钥匙应力反应伴侣蛋白HSP70相关联，并调节其在重新折叠受损蛋白质并将其货物递送到蛋白酶体方面的活性。这些事件会影响细胞存活和凋亡中涉及的几种途径，包括线粒体膜去极化，胱天蛋白酶激活，DNA损伤，细胞周期进展等。在小胶质细胞的HIV-1感染过程中，也可以观察到BAG3的激活，这是一种支持大脑病毒复制的细胞类型。有趣的是，随着siRNA对BAG3的沉默，BAG3的激活似乎增强了细胞的存活率，从而增加了HIV-1感染的小胶质细胞的凋亡率。 BAG3的诱导可能会对HIV-1复制产生负面影响，因为BAG3具有抑制小胶质细胞和星形胶质细胞中HIV-1基因转录的能力。实际上，一旦细胞中降低了BAG3的水平，这些事件可能会逆转。在神经胶质细胞中，这可以在激活人类机会病毒JCV时完成，该病毒的早期蛋白会抑制BAG3转录，并可以减轻BAG3对HIV-1的负面影响并促进凋亡途径。这些观察结果与艾滋病的神经病变有关，作为JCV的复制，这导致艾滋病患者经常看到进行性多焦点白血病（PML）的发展。所有这些观察结果都使我们假设Bag3通过协助细胞在HIV-1的初始感染中生存，可以在转化细胞成为该病毒的长期储层中发挥关键作用。使用此概念，我们计划研究CNS细胞中BAG3差异调节的分子事件，确定BAG3抑制HIV-1表达并复制的途径，研究通过抑制BAG3对HIV-1表达的JCV的影响，并确定与BAG3介导的细胞中有关HIV-1感染的细胞中涉及的机制。我们将采用分子，细胞和病毒学方法来解决这些问题，并通过对HIV-1 CNS疾病患者的临床样本进行免疫组织化学评估来检查我们发现的生物学相关性。

项目成果

Regulation of human neurotropic JC virus replication by alternative splicing factor SF2/ASF in glial cells.

• DOI: 10.1371/journal.pone.0014630
• 发表时间: 2011-01-31
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Sariyer IK;Khalili K
• 通讯作者: Khalili K

BAG3 protein regulates caspase-3 activation in HIV-1-infected human primary microglial cells.

• DOI: 10.1002/jcp.21604
• 发表时间: 2009-02
• 期刊: Journal of cellular physiology
• 影响因子: 5.6
• 作者: Rosati A;Khalili K;Deshmane SL;Radhakrishnan S;Pascale M;Turco MC;Marzullo L
• 通讯作者: Marzullo L

Extinction of Tumor Antigen Expression by SF2/ASF in JCV-Transformed Cells.

• DOI: 10.1177/1947601911424578
• 发表时间: 2011-07-01
• 期刊: Genes & cancer
• 作者: Uleri, Elena;Beltrami, Sarah;Sariyer, Ilker Kudret
• 通讯作者: Sariyer, Ilker Kudret