Monocyte Traffic and Neuropathogenesis of AIDS

描述（由申请人提供）：本次竞争性续期申请的重点是神经艾滋病患者中枢神经系统（CNS）中单核细胞驱动CNS疾病。在之前的资助期内，我们确定了CDS淋巴细胞控制SIV脑炎（SIVE）发展的作用，建立了神经aids的快速和一致的中枢神经系统疾病模型，并通过MR光谱证明了激活和感染单核细胞的增加与神经元损伤相关。抗逆转录病毒治疗可轻微降低血浆病毒，迅速逆转单核细胞活化和神经元损伤。在即将到来的资助期，我们的重点是识别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异性单核细胞亚群。我们假设特定的单核细胞亚群随着中枢神经系统疾病而扩大和驱动，并随着直接靶向单核细胞或单核细胞交通的免疫调节剂而减少。我们提出了三个具体目标来研究我们的假设。目的1的研究将选择性地鉴定免疫表型和功能上不同的单核细胞亚群在SIV感染的神经艾滋病动物中扩增，并确定调节其扩增的因素。aim 2的研究建议在正常和SIV感染的动物中使用白细胞分离，直接评估特定单核细胞亚群在正常、病毒血症和SIV感染的CNS疾病动物中转运到CNS的作用。aim 3中的研究建议使用抗vla4和vla1的单克隆抗体，以及选择性靶向cd14 + cd16 +单核细胞的多胺合成药理学抑制剂，以确定活跃的单核细胞运输在神经aids中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.