Monocyte-Macrophage Dynamics in NeuroAIDS

神经艾滋病中的单核细胞-巨噬细胞动力学

• 批准号: 8230669
• 负责人: JAY RAPPAPORT
• 金额: $ 57.08万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8230669
• 关键词: AIDS Dementia Complex; AIDS neuropathy; Acquired Immunodeficiency Syndrome; Affinity; Animals; Antigens; Antiviral Agents; Biological Assay; Blood Circulation; Bromodeoxyuridine; CD14 Antigen; CD14 gene; CD16 Antigens; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Count; Cells; Central Nervous System Diseases; Characteristics; Cognition Disorders; Control Animal; Development; Disease; Encephalitis; Exhibits; FCGR3B gene; Fluorescent Dyes; Frequencies; Gene Chips; HIV; HIV Infections; Health; Homeostasis; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Immunosuppression; Impairment; In Vitro; Individual; Infection; Investigation; Kinetics; Label; Macaca mulatta; Minor; Modeling; Myelogenous; Neurologic; Organ; Pathogenesis; Patients; Peripheral Nervous System; Peripheral Nervous System Diseases; Phenotype; Plasma; Play; Population; Process; Production; Regulatory Pathway; Relative (related person); Role; SIV; SIV encephalitis; Staining method; Stains; System; T cell response; T-Cell Depletion; T-Lymphocyte; Testing; Time; Tissues; Viral; Viral Load result; Virus; base; chemokine; cytokine; enzyme linked immunospot assay; hemoglobin-haptoglobin receptor; human subject; in vivo; longitudinal analysis; macrophage; monocyte; motor disorder; peripheral blood; public health relevance; therapy development; trafficking

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.

描述(由申请人提供)：艾滋病毒相关的中枢神经系统疾病是相当大比例的艾滋病毒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，艾滋病毒痴呆症，以及周围神经病。艾滋病的神经系统并发症发生的部分原因是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证实了HIV感染患者和SIV感染猕猴外周血中单核细胞亚群(CD14+/CD163+/CD16+)的积聚。循环中的这些单核细胞似乎是HIV/SIV脑炎中血管周围巨噬细胞聚集的前驱细胞。在健康个体中，这个亚群通常很低，似乎扩大到与HIV/SIV血浆病毒载量相关的程度，与CD4+T细胞计数成反比。根据这些细胞的表型，在艾滋病中观察到的免疫抑制，以及关于不同的单核/巨噬细胞亚群的表型和功能的新信息，我们认为CD14+/CD163+/CD16+单核细胞在艾滋病中聚集，在免疫极化中发挥作用，可能参与了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感染恒河猴的模型来研究SIV感染在同时结合两种体内细胞追踪方法改变单核/巨噬细胞动力学方面的后果。我们将利用CFSE荧光染料和BrdU标记的方法来研究SIV感染、SIV感染/CD8+T细胞耗尽和健康对照动物的单核/巨噬细胞动力学。为了确定仅可归因于CD8+T细胞耗竭的潜在影响，并进一步了解正常的动态平衡过程，还将研究未感染的CD8+T细胞耗尽的动物。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分析，以及使用多重(Luminex)和Affymetrix基因芯片方法表征细胞因子、趋化因子以及调节途径。这些研究可能为艾滋病和神经艾滋病中单核/巨噬细胞靶向治疗的研究和开发提供新的途径。 公共卫生相关性：艾滋病毒感染是世界范围内的主要问题。单核/巨噬细胞系统不仅为病毒提供了稳定的储存库，而且这些细胞负责将艾滋病毒传播到中枢神经系统和其他组织。这些研究可能会对我们理解单核/巨噬细胞在中枢神经系统疾病发生发展中的作用产生重大影响，同时探讨它们在艾滋病免疫功能障碍中的作用。