Suppression HIV-1 in CNS by novel protein-ST John's Wort

新型蛋白质-圣约翰草抑制中枢神经系统中的 HIV-1

• 批准号: 7167359
• 负责人: SHOHREH AMINI
• 金额: $ 32.06万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7167359
• 关键词: AIDS /HIV neuropathy; HIV infections; RNA interference; St Johns wort; T lymphocyte; alternative medicine; antiAIDS agent; astrocytes; cyclins; embryo /fetus cell /tissue; gene expression; host organism interaction; human immunodeficiency virus 1; human tissue; macrophage; medicinal plants; microglia; neuropharmacology; nuclear factor kappa beta; tissue /cell culture; transcription factor; virus genetics; virus infection mechanism; virus protein; virus replication

DESCRIPTION (provided by applicant): Suppression of HIV-1 in CNS by a novel protein from St. John's Wort.+ The transcription process is the first step in the reactivation of HIV-1 genome that eventually leads to complete cytolytic destruction of host cells. As such, since the discovery of HIV-1 there has been a major effort to understand the mechanism by which the viral genome is transcribed and to identify the therapeutic strategies to intervene in this process. In the central nervous system (CNS), microglia, macrophages, and astrocytes are the primary cells that harbor HIV-1 and support, albeit to various degrees, expression and replication of the HIV-1 genome. Earlier studies have ascribed important roles for several transcription factors such as the C/EBPa family, NFkB (p50/p65), and the viral transactivator, Tat, and the late auxiliary protein, Vpr, in these cells. Further, it was evident that cross-interplay of these factors with each other and their specific partners are the key determinants of their activities. Of particular interest was the notion that some of the pathways that are involved in the activation of the HIV-1 genome by Tat also engaged in dysregulated expression of host factors that are implicated in the neuropathogenesis of AIDS. Thus, targeting of these specific viral and cellular activators may provide an effective tool for blocking direct and indirect pathways that are involved in AIDS/CNS injury. In this research proposal we build on our preliminary data indicating that a novel protein, p27SJ, derived from a callus culture of Hypericum perforatum (also known as St. John's Wort) has the ability to physically and functionally interact with Tat and C/EBPa, and impairs their activities upon the HIV-1 genome in microglia and astrocytes. We propose to launch a comprehensive study to 1) unravel the molecular basis of p27SJ suppression of HIV-1 by assessing the interplay of C/EBPa and Tat, and their impact on the overall contribution of various transcription factors that are implicated in LTR transcription. The outcome of this molecularly based project will provide important information and biological tools which, in turn, can be utilized in the future to devise therapeutic tools for halting viral gene expression and replication, and blocking Tat-induced stimulation of pro-inflammatory factors which are implicated in the pathogenesis of AIDS associated neurological problems

描述（由申请人提供）：由圣约翰麦芽汁的一种新蛋白抑制CNS中的HIV-1。+转录过程是HIV-1基因组重新激活的第一步，最终导致宿主细胞的细胞溶解破坏。因此，自从发现HIV-1以来，已经有一项重大努力来了解病毒基因组被转录的机制，并确定干预此过程的治疗策略。在中枢神经系统（CNS）中，小胶质细胞，巨噬细胞和星形胶质细胞是携带HIV-1和支持的主要细胞，尽管在各种程度上，HIV-1基因组的表达和复制。较早的研究已归因于几种转录因子，例如C/EBPA家族，NFKB（p50/p65）以及这些细胞中的病毒式反式激活剂TAT和晚期辅助蛋白VPR。此外，很明显，这些因素彼此及其特定伴侣的交叉互动是其活动的关键决定因素。特别令人感兴趣的是，TAT参与HIV-1基因组激活的某些途径也参与与艾滋病神经发作有关的宿主因子的失调表达。因此，靶向这些特定的病毒和细胞活化剂可能会提供有效的工具，以阻止参与艾滋病/中枢神经系统损伤的直接和间接途径。在这项研究建议中，我们基于我们的初步数据，表明一种新型蛋白质P27SJ源自Hypericum Perforatum的愈伤组织（也称为St. John's Wort），具有与TAT和C/C/C/EBPA的物理和功能相互作用的能力，并损害其对小胶质细胞中HIV-1基因组的活动。我们建议通过评估C/EBPA和TAT的相互作用及其对LTR转录中涉及的各种转录因子的总体贡献的影响，从而启动一项全面研究。这个基于分子的项目的结果将提供重要的信息和生物学工具，而这些信息和生物学工具反过来又可以在将来使用来设计治疗工具，以停止病毒基因表达和复制，并阻止TAT诱导的刺激促炎性因素，这些因素与AIDS相关神经问题的病原体有关