Pathophysiology of AIDS Associated PML

艾滋病相关 PML 的病理生理学

• 批准号: 6790528
• 负责人: Luis Del Valle
• 金额: $ 26.34万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-15 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6790528
• 关键词: AIDS; Polyomavirus hominis 2; brain; comorbidity; cytokine; disease /disorder etiology; disease /disorder proneness /risk; gene expression; genetic regulation; genetic regulatory element; hamsters; host organism interaction; human immunodeficiency virus; human tissue; immunocytochemistry; molecular pathology; oligodendroglia; postmortem; progressive multifocal leukoencephalopathy; protein structure function; tissue /cell culture; transcription factor; transforming growth factors; tumor necrosis factor alpha; virus infection mechanism; virus protein

DESCRIPTION: (Provided by applicant) PML is a subacute, fatal demyelinating disease of the Central Nervous System (CNS) that affects individuals with underlying defects in immunity. This once considered rare disease is more frequently seen after the AIDS pandemic. The significantly higher incidence of PML in patients with AIDS than in any other immunosuppressive condition suggests that there may be an interaction between HIV-1 and JC Virus. Previous in vitro studies have demonstrated direct intercommunication between HIV-1 and JCV through the HIV-1 encoded regulatory protein Tat. This interaction may also be mediated by cytokines and transcription factors. Although there is no strong evidence for the infection of oligodendrocytes by HIV- 1, it is postulated that soluble Tat released from the HIV-l infected cells in the CNS such as microglia, can be taken up by the neighboring uninfected cells, including oligodendrocytes harboring the opportunistic JCV. Activation of JCV could also be mediated indirectly through enhanced expression and release of cytokines such as TNF-alpha and TGF-beta from the HIV-1 infected cells. TNF-alpha can induce expression and activity of inducible transcription factors, such as NFkB which increases expression of the JCV genome, via the KB motif positioned in the viral promoter region. On the other hand, TGF-beta, through the SMAD pathway, could also lead to activation and elevated expression of the JCV genome. With this notion, we hypothesize that activation of JCV by Tat could be mediated by localization of Tat in the nucleus of JCV infected oligodendrocytes, and indirectly by altering expression of cytokines, which leads to enhanced activity of NFKB subunits p50 and p65, and TGF-beta /SMAD in the JCV infected oligodendrocytes. We will perform cell culture studies to investigate the regulatory pathways, including TNF-a and TGF-beta that upregulate JCV replication and we will also carry out immunohistochemical studies in human AIDS and non- AIDS related PML autopsy specimens to illustrate replication of JCV in oligodendrocytes at the level of NFKB and SMADs, as well as Tat in cells which are infected with JCV. The results from these experiments will provide information to elucidate the role of HIV-1 and its transactivator protein Tat in the activation of JC Virus, through direct and/or indirect mechanisms, and therefore in the development of PML in patients with AIDS.

描述：(申请人提供)PML是一种亚急性、致命的脱髓鞘 中枢神经系统(CNS)疾病，影响患有 豁免权的潜在缺陷。这种曾经被认为是罕见的疾病 在艾滋病大流行后经常出现。明显更高的发病率 艾滋病患者的PML比任何其他免疫抑制状态下的PML 提示HIV-1和JC病毒之间可能存在相互作用。上一首 体外研究表明，HIV-1和HIV-1之间的直接相互联系 JCV通过HIV-1编码的调控蛋白Tat。这种交互还可以 由细胞因子和转录因子介导。虽然没有很强的 HIV-1感染少突胶质细胞的证据，推测 中枢神经系统内HIV-L感染细胞释放的可溶性TAT 小胶质细胞，可被邻近的未感染细胞摄取，包括 少突胶质细胞存在机会性JCV。JCV的激活也可以 通过增强细胞因子的表达和释放间接介导 如来自HIV-1感染细胞的肿瘤坏死因子-α和转化生长因子-β。肿瘤坏死因子-α可以 诱导NFkB等可诱导转录因子的表达和活性 通过Kb基序定位于 病毒启动子区域。另一方面，通过SMAD，转化生长因子-β 途径，也可能导致激活和上调JCV的表达 基因组。根据这个概念，我们假设TAT对JCV的激活可能是 Tat基因在JCV感染细胞核内的定位 少突胶质细胞，并间接通过改变细胞因子的表达， 导致NFKB亚基p50和p65以及转化生长因子-β/SMAD活性增强 JCV感染少突胶质细胞。 我们将进行细胞培养研究，以研究调控途径， 包括促进JCV复制的肿瘤坏死因子-α和转化生长因子-β，我们还将 对人类艾滋病和非艾滋病相关的PML进行免疫组织化学研究 尸检标本显示JCV在少突胶质细胞中的复制 JCV感染细胞中NFKB和Smads的水平以及Tat的水平。 这些实验的结果将为阐明 HIV-1及其反式激活蛋白Tat在JC病毒激活中的作用 通过直接和/或间接机制，从而在发展 艾滋病患者中的PML。

项目成果

Identification of HIV-associated progressive multifocal leukoencephalopathy: magnetic resonance imaging and spectroscopy.

HIV 相关进行性多灶性白质脑病的鉴定：磁共振成像和光谱学。

• DOI: 10.1176/jnp.15.1.1
• 发表时间: 2003
• 期刊: The Journal of neuropsychiatry and clinical neurosciences
• 作者: Hurley,RobinA;Ernst,Thomas;Khalili,Kamel;DelValle,Luis;Simone,IsabellaLaura;Taber,KatherineH
• 通讯作者: Taber,KatherineH