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: 8442885
• 负责人: JAY RAPPAPORT
• 金额: $ 52.26万
• 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/8442885
• 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.

描述（由申请人提供）：HIV相关的中枢神经系统疾病代表了很大比例的艾滋病毒感染者的主要健康问题。这些疾病包括较小的认知和运动障碍，HIV痴呆以及周围神经病。艾滋病的神经系统并发症部分是由于从外周血侵入中央和周围神经系统组织的巨噬细胞的侵袭。我们以前的研究已经确定了HIV感染和感染SIV感染的Rhesus猕猴在外周血中单核细胞子集（CD14+/CD163+/CD16+）的积累。这些循环中的单核细胞似乎代表了在HIV/SIV脑炎中积累的血管周围巨噬细胞的前体。通常在健康个体中，该子集似乎扩展到与HIV/SIV血浆病毒载量相关的程度，并且与CD4+ 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，以及有关不同单核细胞/巨噬细胞亚群的表型和功能的新信息，我们建议CD14+/CD163+/CD163+/CD16+单核细胞在AID中积累的辅助物在AID中积累，在免疫极化中起作用，可能在免疫剂和AIDS中发挥作用。在本应用中提出的研究中，我们将利用两种体内细胞跟踪方法同时组合SIV感染的SIV感染猕猴模型来研究SIV感染在改变单核细胞/巨噬细胞动力学中的后果。利用CFSE荧光染料和BRDU标记的一种方法将用于研究SIV感染，SIV感染/CD8+ T细胞的单核细胞/巨噬细胞动力学，耗尽的动物和健康对照动物。为了确定仅归因于CD8+ T细胞耗竭的潜在影响并进一步了解正常的稳态过程，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+单核细胞是否使用抗原特异性免疫测定表现出免疫极化，以及使用多种形式（Luminex）和Affymetrix基因芯片方法的细胞因子，趋化因子以及调节途径的表征。此处提出的研究可能为研究和开发针对艾滋病和神经辅助物中单核细胞/巨噬细胞的疗法的发展提供了新的途径。