Monocyte Traffic and Neuropathogenesis of AIDS

描述(由申请人提供)：本次竞争性更新申请的重点是单核细胞在神经艾滋病患者中驱动中枢神经系统(CNS)疾病。在之前的资助期间，我们明确了CDS淋巴细胞在SIV脑炎(SIVE)发展中的控制作用，建立了一种快速和一致的神经艾滋病中枢神经系统疾病模型，并通过磁共振波谱证实了与神经元损伤相关的激活和感染单核细胞的增加。抗逆转录病毒治疗略微降低血浆病毒，迅速逆转单核细胞激活和神经元损伤。我们在即将到来的资助期的重点是确定与免疫或单核细胞靶向治疗后的神经元损伤和恢复相关的特定单核细胞亚群。我们假设，特定的单核细胞亚群随着中枢神经系统疾病的发展而扩大并驱动，而随着免疫调节剂直接针对单核细胞或单核细胞交通而减少。我们提出了三个具体目标来研究我们的假设。目标1中的研究将有选择地识别SIV感染的神经艾滋病动物中扩增的免疫表型和功能不同的单核细胞亚群，并确定调节其扩增的因素。目标2中的研究建议在正常和SIV感染的动物中使用白细胞分离，以直接评估在正常、病毒症和SIV感染的CNS疾病动物中特定的单核细胞亚群运输到中枢神经系统的作用。Aim 3的研究建议使用抗VLA-4和VLA-1的单抗，以及选择性靶向CD14+CD16+单核细胞的多胺合成的药物抑制剂，以确定活跃的单核细胞转运在神经艾滋病持续神经元损伤中的作用。

DESCRIPTION (provided by applicant): The focus of this competitive renewal application is on monocytes driving CNS disease in the central nervous system (CNS) in neuroAIDS. In the previous funding period, we defined the role of CDS lymphocytes controlling the development of SIV encephalitis (SIVE), developed a model of rapid and consistent CNS disease of neuroAIDS, and demonstrated an increase of activated and infected monocytes that correlate with neuronal injury demonstrated by MR spectroscopy. Antiretroviral therapy that slightly decreased plasma virus, rapidly reversed monocyte activation and neuronal injury. Our focus in the upcoming funding period is to identify specific monocyte subsets that correlate with neuronal injury and recovery following immune- or monocyte-targeted therapy. We hypothesize that specific subsets of monocytes expand with and drive CNS disease, and decrease with immune modulators directly targeting monocytes or monocyte traffic. We propose 3 specific aims to study our hypothesis. Studies in aim 1 will selectively identify immune- phenotypically and functionally distinct monocyte subsets expanded in SIV infected animals with neuroAIDS and define factors regulating their expansion. Studies in aim 2 propose to use leukapheresis, in normal and SIV infected animals to directly assess the role of specific monocyte subsets to traffic to the CNS in normal, viremic and SIV infected animals with CNS disease. Studies in aim 3 proposed to use monoclonal antibodies against VLA-4 and VLA-1, and a pharmacologic inhibitor of polyamine synthesis that selectively targets CD 14+ CD 16+ monocytes to determine the role of active monocyte traffic contributing to ongoing neuronal injury in neuroAIDS.