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

描述(申请人提供)：用圣约翰麦芽汁中的一种新蛋白抑制中枢神经系统中的HIV-1。+转录过程是重新激活HIV-1基因组的第一步，最终导致宿主细胞的完全溶细胞性破坏。因此，自发现HIV-1以来，人们一直在努力了解病毒基因组转录的机制，并确定干预这一过程的治疗策略。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的主要细胞，并在不同程度上支持HIV-1基因组的表达和复制。早期的研究已将C/EBPA家族、NFkB(p50/p65)、病毒反式激活因子TAT和晚期辅助蛋白VPR等几种转录因子在这些细胞中发挥重要作用。此外，显然，这些因素彼此之间及其特定伙伴之间的交叉相互作用是其活动的关键决定因素。尤其令人感兴趣的是，参与TAT激活HIV-1基因组的一些途径也参与了宿主因子的失调表达，这些宿主因子与艾滋病的神经发病机制有关。因此，靶向这些特定的病毒和细胞激活剂可能为阻断与艾滋病/中枢神经系统损伤有关的直接和间接途径提供有效的工具。在这项研究中，我们基于我们的初步数据，表明从贯叶连翘(又称圣约翰草)愈伤组织培养中提取的一种新蛋白p27SJ具有与TAT和C/EBPA物理和功能相互作用的能力，并损害它们在小胶质细胞和星形胶质细胞中对HIV-1基因组的活性。我们建议启动一项全面的研究，以1)通过评估C/EBPA和TAT的相互作用，以及它们对参与LTR转录的各种转录因子的整体贡献的影响，来揭示p27SJ抑制HIV-1的分子基础。这个以分子为基础的项目的结果将提供重要的信息和生物工具，这些信息和生物工具在未来可以用来设计治疗工具来阻止病毒基因的表达和复制，并阻止tat诱导的促炎因子的刺激，这些因子与艾滋病相关的神经问题的发病机制有关。

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