Monocyte Traffic and Neuropathogenesis of AIDS

描述（由申请人提供）：本竞争性更新申请的重点是在neuroAIDS中驱动中枢神经系统（CNS）疾病的单核细胞。在上一个资助期，我们定义了CDS淋巴细胞控制SIV脑炎（SIVE）发展的作用，开发了一个快速和一致的CNS疾病neuroAIDS模型，并证明了与MR波谱显示的神经元损伤相关的活化和感染单核细胞的增加。抗逆转录病毒治疗，轻微降低血浆病毒，迅速逆转单核细胞活化和神经元损伤。我们在即将到来的资助期间的重点是确定与免疫或单核细胞靶向治疗后神经元损伤和恢复相关的特定单核细胞亚群。我们假设单核细胞的特定亚群随着CNS疾病的发生而扩大并驱动CNS疾病，而随着直接靶向单核细胞或单核细胞运输的免疫调节剂的减少而减少。我们提出了三个具体目标来研究我们的假设。目的1中的研究将选择性地鉴定在患有neuroAIDS的SIV感染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子。目标2中的研究建议在正常和SIV感染动物中使用白细胞分离术，直接评估特定单核细胞亚群在正常、病毒血症和SIV感染CNS疾病动物中运输至CNS的作用。目的3中的研究提出使用针对VLA-4和VLA-1的单克隆抗体，以及选择性靶向CD 14+ CD 16+单核细胞的多胺合成的药理学抑制剂，以确定有助于神经AIDS中持续神经元损伤的活性单核细胞运输的作用。

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.