Monocyte-Macrophage Dynamics in NeuroAIDS

描述（由申请方提供）：HIV相关CNS疾病是相当大比例的HIV感染者的主要健康问题。这些疾病包括轻微的认知和运动障碍、HIV痴呆以及周围神经病变。AIDS的神经系统并发症的发展，部分是由于来自外周血的巨噬细胞侵入中枢和外周神经系统组织。我们以前的研究已经确定了单核细胞亚群（CD 14 +/CD 163 +/CD 16+）在HIV感染和SIV感染的恒河猴患者外周血中的积累。循环中的这些单核细胞似乎代表了HIV/SIV脑炎中血管周围巨噬细胞积聚的前体。在健康个体中通常较低，该亚群似乎扩增到与HIV/SIV血浆病毒载量相关的程度，并且与CD 4 + T细胞计数成反比。基于这些细胞的表型，在艾滋病中观察到的免疫抑制，以及关于不同的单核细胞/巨噬细胞亚群的表型和功能的新信息，我们提出，CD 14 +/CD 163 +/CD 16+单核细胞在艾滋病中积累，在免疫极化中发挥作用，并可能有助于艾滋病的免疫发病机制。在本申请中提出的研究中，我们将利用SIV感染的恒河猴模型，使用两种体内细胞追踪方法的同时组合来研究SIV感染在改变单核细胞/巨噬细胞动力学中的后果。将采用利用CFSE荧光染料和BrdU标记的方法来研究SIV感染、SIV感染/CD 8 + T细胞耗尽和健康对照动物中的单核细胞/巨噬细胞动力学。为了鉴定仅归因于CD 8 + T细胞耗竭的潜在效应并进一步了解正常的稳态过程，还将研究未感染的CD 8 + T细胞耗竭动物。我们将使用抗原特异性免疫测定进一步确定CD 14 +/CD 163 +/CD 16+单核细胞是否表现出免疫极化，并使用多重（Luminex）和Affyphin基因芯片方法表征细胞因子、趋化因子以及调控途径。本文提出的研究可能为研究和开发针对艾滋病和神经艾滋病单核细胞/巨噬细胞的治疗提供新的途径。

DESCRIPTION (provided by applicant): HIV associated CNS disorders represent a major health problem in a significant proportion of HIV infected individuals. These disorders include minor cognitive and motor disorders, HIV dementia, as well as peripheral neuropathy. The neurologic complications of AIDS develop, in part, because of the invasion of macrophages derived from peripheral blood into the central and peripheral nervous system tissues. Our previous studies have identified the accumulation of a monocyte subset (CD14+/CD163+/CD16+) in peripheral blood in patients with HIV infection and SIV infected rhesus macaques. These monocytes in circulation appear to represent precursors of the perivascular macrophages accumulating in HIV/SIV encephalitis. Normally low in healthy individuals, this subset appears to expand to a degree correlating with HIV/SIV plasma viral load, and inversely with CD4+ T cell count. Based on the phenotype of these cells, the immunosuppression observed in AIDS, together with new information regarding the phenotype and function of distinct monocyte/macrophages subsets, we propose that CD14+/CD163+/CD16+ monocytes accumulating in AIDS, play a role in immune polarization and may contribute to the immunopathogenesis of AIDS. In the studies proposed in this application, we will utilize the SIV infected rhesus macaque model to study the consequences of SIV infection in altering monocyte/macrophage dynamics using the simultaneous combination of two in vivo cell tracking approaches. An approach utilizing CFSE fluorescent dye and BrdU labeling will be employed to study monocyte/macrophage dynamics in SIV infected, SIV infected/CD8+ T cell depleted, and healthy control animals. In order to identify potential effects solely attributable to the CD8+ T cell depletion and to further understand normal homeostatic processes, uninfected CD8+ T cell depleted animals will also be studied. We will further determine if the CD14+/CD163+/CD16+ monocyte exhibits immune polarization using antigen specific immune assays and the characterization of cytokines, chemokines as well as regulatory pathways using multiplex (Luminex) and Affymetrix gene chip approaches. The studies proposed here may provide new avenues for investigation and the development of therapies targeting the monocyte/macrophage in AIDS and NeuroAIDS.