HIV-1 Associated Dementia: Concomitant Roles of Vpr and Cellular Factors

描述(由申请人提供)：HIV-1相关的神经发病机制有两个不同的观察结果。第一个问题涉及HIV-1感染者显著的认知和运动功能障碍。第二个问题与没有感染HIV-1病毒的神经元有关。这表明艾滋病患者的痴呆可能是HIV-1编码蛋白(Env、Tat、Nef和VPR)和宿主细胞因素的直接和间接作用的结果。痴呆症发生和发展的潜在机制尚不清楚。本应用的目的是阐明HIV-1vpr在神经发病机制中的作用。在感染者中，VPR以细胞相关、病毒粒子相关以及细胞和病毒粒子不存在的形式存在。此外，穿透细胞膜的能力使VPR有可能直接对未感染的旁观者(如神经元)造成损害。此外，VPR还通过感染靶细胞释放的细胞因子间接失调旁观者细胞。在此基础上，我们假设VPR有可能促进神经元的凋亡和功能障碍。为了阐明痴呆的分子事件，我们建议以适当的人类原代细胞培养为模型来分析VPR的作用。为了实现这些目标，我们建议：(I)直接确定vpr介导的神经元丢失和功能障碍的机制(S)；(Ii)在靶细胞中识别vpr差异调节的细胞辅助因子和神经炎性分子；以及(Iii)使用来自中枢神经系统的自然产生的vpr变体来确定vpr与神经发病的结构-功能关系。 公共卫生相关性：高效抗逆转录病毒疗法(HAART)在治疗HIV-1感染者方面取得了显著改善，尽管HAART已可用，但神经认知障碍影响着50%-70%的HIV-1感染者。HIV相关性痴呆(HAD)的高发病率是由于病毒蛋白引起的神经元功能障碍以及感染细胞向局部环境释放的炎症因子所致。因此，针对病毒和神经炎性因子的联合治疗将是可取的。本研究的重点是了解病毒和宿主细胞因子在神经发病机制中的作用，以确定中枢神经系统中HIV-1的新靶点和设计新的治疗方法。

DESCRIPTION (provided by applicant): HIV-1 associated neuropathogenesis is characterized by two distinct observations. The first concerns the notable cognitive and motor dysfunction in HIV-1 infected individuals. The second relates to the lack of infection of neurons by HIV-1. This suggests that the dementia in AIDS patients might be the result of a combination of both direct and indirect effects of HIV-1 encoded proteins (Env, Tat, Nef and Vpr) and host cellular factors. The mechanisms underlying the onset and progression of dementia are poorly understood. The goal of this application is to elucidate the contribution of HIV-1 Vpr to neuropathogenesis. In the infected individuals, Vpr is present in cell-associated, virion-associated and cell and virion-free forms. Further, the ability to traverse through cell membrane endows Vpr the potential to cause damage directly in uninfected bystanders such as neurons. Furthermore, Vpr is also known to indirectly dysregulate bystander cells through cellular factors released from infected target cells. Based on this, we hypothesize that Vpr has the potential to contribute to neuronal apoptosis and dysfunction. To elucidate the molecular events underlying dementia, we propose to analyze the effects of Vpr using appropriate human primary cells in culture as a model. To achieve these goals we propose to: (i) determine the mechanism(s) involved in Vpr mediated neuronal loss and dysfunction directly; (ii) identify the cellular cofactors and neuroinflammatory molecules differentially regulated by Vpr in target cells; and (iii) identify the structure-function relation of Vpr to neuropathogenesis using naturally occurring Vpr variants from CNS compartment. PUBLIC HEALTH RELEVANCE: Dramatic improvements in treating HIV-1 infected individuals have been attained with Highly Active Anti-Retroviral Therapy (HAART), and despite the availability of HAART, neurocognitive disorders affect 50-70% of the HIV-1 infected individuals. High incidence of HIV-Associated Dementia (HAD) is due to the neuronal dysfunction caused by the viral proteins as well as the inflammatory factors released by the infected cells into the local environment. Therefore, a combination therapy targeting both viral and neuroinflammatory factors would be desirable. This study focuses on understanding the role of viral and host cellular factors in neuropathogenesis toward identifying novel targets and designing new therapeutics against HIV-1 in the central nervous system.