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

描述（由申请人提供）：一种来自圣约翰草的新蛋白在中枢神经系统中抑制HIV-1。转录过程是HIV-1基因组再激活的第一步，最终导致宿主细胞的完全细胞溶解破坏。因此，自从发现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，尽管在不同程度上支持HIV-1基因组的表达和复制。早期的研究认为，C/EBPa家族、NFkB （p50/p65）、病毒反激活因子Tat和晚期辅助蛋白Vpr等转录因子在这些细胞中发挥着重要作用。此外，很明显，这些因素彼此之间及其具体伙伴之间的相互作用是其活动的关键决定因素。特别令人感兴趣的是，一些与Tat激活HIV-1基因组有关的途径也参与了与艾滋病神经发病机制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激活剂可能为阻断艾滋病/中枢神经系统损伤的直接和间接途径提供了有效的工具。在这项研究计划中，我们建立在我们的初步数据的基础上，表明从贯叶连翘（也称为圣约翰草）愈伤组织培养中提取的一种新蛋白p27SJ具有与Tat和C/EBPa在物理和功能上相互作用的能力，并削弱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。我们建议开展一项全面的研究，通过评估C/EBPa和Tat的相互作用，以及它们对LTR转录中涉及的各种转录因子的总体贡献的影响，揭示p27SJ抑制HIV-1的分子基础。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，反过来，可以在未来用于设计治疗工具，以阻止病毒基因表达和复制，并阻断tat诱导的促炎因子的刺激，这与艾滋病相关的神经系统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