Monocyte-Macrophage Dynamics in NeuroAIDS

描述（由申请人提供）：HIV相关的中枢神经系统疾病是HIV感染者中相当大比例的主要健康问题。这些疾病包括轻微的认知和运动障碍、艾滋病毒痴呆以及周围神经病变。艾滋病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周围神经系统组织。我们之前的研究已经在HIV感染和SIV感染的恒河猴患者的外周血中发现了单核细胞亚群（CD14+/CD163+/CD16+）的积累。这些循环中的单核细胞似乎代表了在HIV/SIV脑炎中积聚的血管周围巨噬细胞的前体。在健康个体中通常较低，这个亚群似乎扩大到一定程度，与HIV/SIV血浆病毒载量相关，与CD4+ T细胞计数相反。基于这些细胞的表型、在艾滋病中观察到的免疫抑制，以及关于不同单核细胞/巨噬细胞亚群表型和功能的新信息，我们提出CD14+/CD163+/CD16+单核细胞在艾滋病中积累，在免疫极化中起作用，可能参与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，通过同时结合两种体内细胞跟踪方法，研究SIV感染对单核细胞/巨噬细胞动力学的影响。采用CFSE荧光染料和BrdU标记的方法研究SIV感染、SIV感染/CD8+ T细胞缺失和健康对照动物的单核细胞/巨噬细胞动力学。为了确定CD8+ T细胞耗竭的潜在影响，并进一步了解正常的体内平衡过程，未感染的CD8+ T细胞耗竭的动物也将被研究。我们将进一步确定CD14+/CD163+/CD16+单核细胞是否表现出免疫极化，使用抗原特异性免疫测定和细胞因子、趋化因子的表征，以及使用multiplex （Luminex）和Affymetrix基因芯片方法的调控途径。本研究为单核/巨噬细胞治疗艾滋病和神经艾滋病的研究和开发提供了新的途径。

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. PUBLIC HEALTH RELEVANCE: HIV infection is major problem worldwide. The monocyte/ macrophage system not only provides a stable reservoir for the virus, but these cells are responsible for trafficking of HIV into the CNS and other tissues. The studies proposed here may have a major impact on our understanding of the function of the monocyte/macrophage in the development of CNS disease, and at the same time investigate their role in contributing to immune dysfunction in AIDS.