MONOCYTE TRAFFIC AND NEUROPATHOGENESIS OF AIDS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们的重点是确定特定的单核细胞亚群，这些亚群与神经艾滋病期间的神经元损伤相关并可以预测。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生而扩大并驱动，而这些亚群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。使用恒河猴可以对疾病的神经发病机制进行受控探索，这些疾病具有艾滋病毒和神经炎症的病理特征，与人类神经艾滋病的研究直接相关。在SIV和HIV感染期间，在中枢神经系统中被证明是生产性感染的绝大多数细胞是单核/巨噬细胞系的细胞。在感染过程中，血管周围巨噬细胞聚集，表达CD14和CD16，其中一些是生产性感染，并在骨髓、血液和脑中表达增殖细胞核抗原，这是感染细胞的标志。这些细胞的积聚可以在感染后的早期、几天到几周内发现，并伴随着晚期艾滋病。有充分的理由相信，骨髓和血液中的单核细胞群体可能是血管周围巨噬细胞的来源，实际上是随着病毒积累的细胞，即所谓的特洛伊木马细胞。采用CD8耗竭和SIVmac251感染快速、一致的中枢神经系统疾病模型，结合MRS和神经病理学检查，研究持续单核细胞转运在艾滋病期间神经元损伤中的意义。我们确定了特定的单核细胞亚群，在免疫表型和功能上，与神经元损伤相关并可预测。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.