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

描述（由申请人提供）：HIV-1相关神经发病机制的特征在于两种不同的观察结果。第一个问题是HIV-1感染者的认知和运动功能障碍。第二个原因是神经元没有受到HIV-1的感染。提示艾滋病患者的痴呆可能是HIV-1编码蛋白Env、达特、Nef和Vpr与宿主细胞因子直接和间接共同作用的结果。痴呆症的发病和进展的机制知之甚少。该应用的目标是阐明HIV-1 Vpr对神经发病机制的贡献。在受感染的个体中，Vpr以细胞相关、病毒体相关以及无细胞和病毒体的形式存在。此外，穿过细胞膜的能力赋予Vpr直接在未感染的旁观者如神经元中引起损伤的可能性。此外，还已知Vpr通过从感染的靶细胞释放的细胞因子间接失调旁观者细胞。基于此，我们假设Vpr具有促进神经元凋亡和功能障碍的潜力。为了阐明痴呆症的分子事件，我们建议使用适当的人类原代细胞培养作为模型来分析Vpr的影响。为了实现这些目标，我们建议：（i）确定Vpr介导的神经元损失和功能障碍直接参与的机制;（ii）确定靶细胞中Vpr差异调节的细胞辅因子和神经炎性分子;（iii）使用CNS隔室中天然存在的Vpr变体确定Vpr与神经发病机制的结构-功能关系。 公共卫生相关性：使用高效抗逆转录病毒疗法（HAART）已经实现了治疗HIV-1感染个体的显著改善，并且尽管HAART可用，但神经认知障碍影响50-70%的HIV-1感染个体。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释放到局部环境中的炎症因子。因此，靶向病毒和神经炎性因子的联合疗法将是期望的。这项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，以确定新的靶点并设计新的治疗方法来对抗中枢神经系统中的HIV-1。

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.