Pathophysiology of AIDS Associated PML

艾滋病相关 PML 的病理生理学

• 批准号: 6661953
• 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 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6661953
• 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：（由申请人提供）PML 是一种亚急性、致命性脱髓鞘病 影响个体的中枢神经系统（CNS）疾病 潜在的免疫缺陷。这种曾经被认为是罕见的疾病更 艾滋病流行后经常出现。发病率明显较高 艾滋病患者的 PML 高于任何其他免疫抑制疾病患者 表明 HIV-1 和 JC 病毒之间可能存在相互作用。以前的 体外研究表明 HIV-1 和 HIV-1 之间可以直接相互交流 JCV通过HIV-1编码调节蛋白Tat。这种互动也可能 由细胞因子和转录因子介导。虽然没有强者 少突胶质细胞被 HIV-1 感染的证据，假设 CNS中HIV-1感染细胞释放的可溶性Tat，例如 小胶质细胞可以被邻近的未感染细胞吸收，包括 少突胶质细胞携带机会性 JCV。 JCV 的激活还可以 通过增强细胞因子的表达和释放来间接介导 例如来自 HIV-1 感染细胞的 TNF-α 和 TGF-β。 TNF-α可以 诱导诱导转录因子（例如 NFkB）的表达和活性 通过位于 的 KB 基序增加 JCV 基因组的表达 病毒启动子区。另一方面，TGF-β通过SMAD 途径，也可能导致 JCV 的激活和表达升高 基因组。有了这个概念，我们假设 Tat 对 JCV 的激活可能是 由 Tat 在 JCV 感染细胞核中的定位介导 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 TGF-beta /SMAD 的活性增强 JCV感染的少突胶质细胞。 我们将进行细胞培养研究来调查调控途径， 包括上调 JCV 复制的 TNF-a 和 TGF-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 尸检标本以说明 JCV 在少突胶质细胞中的复制 感染 JCV 的细胞中 NFKB 和 SMAD 以及 Tat 的水平。 这些实验的结果将提供信息来阐明 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，因此在发展 艾滋病患者的 PML。