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

描述（由申请方提供）：来自圣约翰草的一种新蛋白对CNS中HIV-1的抑制作用。+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完全溶细胞破坏。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，在这些细胞中，几种转录因子如C/EBPa家族、NF κ B（p50/p65）、病毒反式激活因子达特和晚期辅助蛋白Vpr具有重要作用。此外，很明显，这些因素相互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这样一种观点，即参与达特激活HIV-1基因组的一些途径也参与了与AIDS神经发病机制有关的宿主因子的表达失调。因此，靶向这些特定的病毒和细胞活化剂可以提供一种有效的工具，用于阻断参与AIDS/CNS损伤的直接和间接途径。在这项研究中，我们建立在我们的初步数据表明，一种新的蛋白质，p27 SJ，来自愈伤组织培养的贯叶连翘（也称为圣约翰草）具有物理和功能相互作用的能力与达特和C/EBPa，并削弱其活动的HIV-1基因组中的小胶质细胞和星形胶质细胞。我们建议开展一项全面的研究，1）通过评估C/EBPa和达特的相互作用，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，阐明p27 SJ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学工具，反过来，这些信息和工具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，这些促炎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