MONOCYTE TRAFFIC AND THE NEUROPATHOGENESIS OF AIDS

单核细胞运输和艾滋病的神经发病机制

• 批准号: 6505415
• 负责人: KENNETH C WILLIAMS
• 金额: $ 5万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6505415
• 关键词: AIDS /HIV neuropathy; CD14 molecule; CD16 molecule; Macaca mulatta; biological models; blood brain barrier; cell type; confocal scanning microscopy; disease /disorder model; genotype; helper T lymphocyte; immunocytochemistry; immunofluorescence technique; macrophage; monocyte; neuropathology; pathologic process; phenotype; regulatory gene; simian immunodeficiency virus; virus DNA; virus RNA; virus load; virus protein; virus replication

Brain macrophages are targets of HIV/SIV infection in the CNS. We have shown that perivascular brain macrophages are a major target of SIV infection in animals with SIV encephalitis (SIVE). The perivascular macrophage population has a similar immunophenotype to circulating PBMC's observed in the blood of HIV infected humans with dementia (CD14/CD16/CD69 positive). Using a model of CD8 depletion with SIV infection that results in a high incidence of SIVE, we observe significant perivascular macrophage accumulation. We hypothesize that a distinct, identifiable population of infected blood monocyte/macrophages similar to perivascular cell in the brain traffics to the CNS and that this population is held in check by CD8+ lymphocytes. To test this hypothesis we will: Examine the CNS of SIV infected animals with and without CD8 depletion to analyze the phenotype, relative cell numbers, and level of infection of subpopulations of brain macrophages at peak viremia and in animals with SIVE. This will be achieved by using immunohistochemistry, double and triple label immunoflourescence with confocal microscopy and quantitative image analysis to examine the expression of CD14/CD16/CD69 and gp120 by perivascular brain macrophages. 2. Identify populations of monocyte/macrophages in the blood of SIV infected macaques that correspond immunophenotypically to perivascular brain macrophages. We propose to examine populations of peripheral blood monocyte/macrophages (CD14+) for a) the number of CD14/CD69+ and CD14/CD16+ cells in the blood and brain during disease development b) the level of SIV infection, and c) env and nef sequences of peripheral blood monocyte/macrophage subpopulations in comparison to brain and other tissue macrophages. 3. Determine the ability of CD8+ lymphocytes to control the number and level of viral infection of blood and brain monocyte/macrophages. Based on the observation of the rapid accumulation of perivascular macrophages in CD8 depleted animals we will study the ability of CD8+ lymphocytes to keep infected blood monocyte/macrophages in check by combinations of : a) direct lysis b) indirect inhibition of viral replication, and c) inhibition of blood monocyte/macrophage traffic through an in vitro BBB model.

脑巨噬细胞是CNS中HIV/SIV感染的靶点。我们已经表明，血管周围的脑巨噬细胞是SIV脑炎（SIVE）动物中SIV感染的主要靶点。血管周围巨噬细胞群具有与在患有痴呆的HIV感染的人的血液中观察到的循环PBMC相似的免疫表型（CD 14/CD 16/CD 69阳性）。使用导致SIVE高发病率的SIV感染的CD 8耗竭模型，我们观察到显著的血管周围巨噬细胞积聚。 我们假设，一个独特的，可识别的人口感染的血液单核细胞/巨噬细胞类似于血管周围的细胞在大脑交通到中枢神经系统，这一人口是在检查由CD 8+淋巴细胞。 为了检验这一假设，我们将：检查CNS的SIV感染的动物和没有CD 8耗竭，以分析表型，相对细胞数，和感染水平的脑巨噬细胞亚群在高峰病毒血症和动物SIVE。这将通过使用免疫组织化学、双标记和三标记免疫荧光与共聚焦显微镜和定量图像分析来检查血管周围脑巨噬细胞的CD 14/CD 16/CD 69和gp 120的表达来实现。 2.鉴定SIV感染猕猴血液中与血管周围脑巨噬细胞免疫表型对应的单核细胞/巨噬细胞群体。 我们建议检查外周血单核细胞/巨噬细胞（CD 14+）的群体，a）疾病发展过程中血液和脑中CD 14/CD 69+和CD 14/CD 16+细胞的数量，B）SIV感染的水平，以及c）与脑和其他组织巨噬细胞相比，外周血单核细胞/巨噬细胞亚群的env和nef序列。 3.确定CD 8+淋巴细胞控制血液和脑单核细胞/巨噬细胞病毒感染数量和水平的能力。 基于对CD 8耗竭动物中血管周围巨噬细胞快速积聚的观察，我们将通过以下组合研究CD 8+淋巴细胞保持受感染的血液单核细胞/巨噬细胞的能力：a）直接裂解B）间接抑制病毒复制，和c）通过体外BB B模型抑制血液单核细胞/巨噬细胞运输。