MONOCYTE TRAFFIC AND NEUROPATHOGENESIS OF AIDS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 我们的重点是确定与neuroAIDS期间神经元损伤相关并可预测神经元损伤的特定单核细胞亚群。 我们假设单核细胞的特定亚群随着中枢神经系统疾病的发生而扩大并驱动中枢神经系统疾病，而这些亚群随着直接靶向单核细胞或单核细胞运输的免疫调节剂而减少。恒河猴的使用允许对具有HIV和神经炎症的病理标志的疾病的神经发病机制进行控制探索，其与人类神经AIDS的研究直接相关。在SIV和HIV感染期间，在CNS中被证明有效感染的绝大多数细胞是单核细胞/巨噬细胞谱系的细胞。随着感染，存在表达CD 14和CD 16的血管周围巨噬细胞的积累，其中一些被有效感染，并且还表达骨髓、血液和脑中感染细胞的标志物PCNA。 这些细胞的积累可以在感染后的早期、数天至数周以及晚期艾滋病中发现。 有充分的理由相信，骨髓和血液中的单核细胞群可能是血管周围巨噬细胞的来源，实际上是与病毒一起积累的细胞，即所谓的特洛伊木马细胞。 使用通过MRS和神经病理学检查评估的导致神经元损伤的快速、一致CNS疾病的CD 8耗竭和SIVmac 251感染模型，研究了AIDS期间持续单核细胞运输对神经元损伤的意义。我们确定了特定的单核细胞亚群，免疫表型和功能，与神经元损伤相关，并预测。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Our focus is to identify specific monocyte subsets that correlate with and are predictive of neuronal injury during neuroAIDS. We hypothesize that specific subsets of monocytes expand with and drive central nervous system disease, and these subsets decrease with immune modulators directly targeting monocytes or monocyte traffic. The use of rhesus macaques permits controlled exploration of the neuropathogenesis of disease that have pathological hallmarks of HIV and neuroinflammation with direct relevance to the studies of human neuroAIDS. During SIV and HIV infection, the vast majority of cells demonstrated to be productively infected in the CNS are cells of the monocyte/macrophage lineage. With infection, there is an accumulation of perivascular macrophages with CD14 and CD16 expression, some of which are productively infected and also express PCNA a marker of infected cells in the bone marrow, blood and brain. The accumulation of these cells can be found early, days-to-weeks post infection, and with terminal AIDS. There is good reason to believe that populations of monocytes in the bone marrow and blood could be a source of perivascular macrophages and indeed cells that accumulate with virus, the so-called Trojan Horse cells. The significance of continued monocyte traffic on neuronal injury during AIDS was studied using a CD8 depletion and SIVmac251 infection model of rapid, consistent CNS disease resulting in neuronal injury as assessed by MRS and neuropathological examination. We identified specific monocyte subsets, immunophenotypically and functionally, that correlate with and are predictive of neuronal injury.