MONOCYTE/MACROPHAGES IN THE PATHOGENESIS OF AIDS IN MACAQUES

单核细胞/巨噬细胞在猕猴艾滋病发病机制中的作用

• 批准号: 8358182
• 负责人: Marcelo J Kuroda
• 金额: $ 5.78万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358182
• 关键词: AIDS diagnosis; Acquired Immunodeficiency Syndrome; Animals; Blood; Bromodeoxyuridine; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; Cellular Structures; Data; Disease Progression; Funding; Grant; HIV; HIV Infections; HIV-1; Human; Immune system; Immunologic Deficiency Syndromes; Individual; Infection; Injection of therapeutic agent; Link; Longitudinal Studies; Macaca; Monkeys; National Center for Research Resources; Natural Immunity; Opportunistic Infections; Pathogenesis; Pathology; Primates; Principal Investigator; Research; Research Infrastructure; Resources; SIV; Source; Survivors; T-Cell Activation; Time; Tissues; United States National Institutes of Health; Viral Load result; adaptive immunity; base; cohort; cost; lymph nodes; macrophage; monocyte

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. It is widely accepted that destruction of CD4+ T cells is the primary cause of immunodeficiency manifested by opportunistic infections in HIV-1 infected humans as well as in SIV-infected macaques. However, the mechanisms that dictate the tempo of disease progression have yet to be elucidated. Not all infected individuals with low CD4 count progress similarly to AIDS. Macrophages, an important cell component of the innate immune system and link between innate and adaptive immunity, are also important targets of HIV/SIV infection. We propose that not only the CD4 T cells but also the monocytes/macrophages are involved in the pathogenesis and progression to AIDS during HIV infection. This is based on our preliminary data that shows high monocyte turnover in SIV infected animals compared to control uninfected animals. Massive destruction of tissue macrophages demonstrated in lymph node of an infected monkey was strongly suggested as the cause of the high monocyte turnover. More importantly, in a longitudinal study of a small cohort of four SIV-infected monkeys, the animal that demonstrated early high and sustained monocyte turnover was a rapid progressor and died with AIDS despite similar levels of T cell activation, high viral load and CD4 counts compared to the other animals in the cohort. The notion that monocyte turnover is important in AIDS progression was strongly supported by the fact that when either all chronically infected animals that died with AIDS (diagnosed by pathology) or animals that are still alive were analyzed for the survivor time after BrdU injection, the only parameter that predicted progression to AIDS with statistical significance was high monocyte turnover. Our hypothesis is that the progressive destruction of tissue macrophages by SIV/HIV is one of the major factors that dictate AIDS disease progression. A corollary to this hypothesis is that the high monocyte turnover in blood is a result of massive destruction of tissue macrophages and may be a predictor of AIDS disease progression.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 人们普遍认为，CD 4 + T细胞的破坏是HIV-1感染的人以及SIV感染的猕猴中机会性感染所表现的免疫缺陷的主要原因。然而，决定疾病进展克里思的机制尚未阐明。并非所有CD 4计数低的感染者都与艾滋病相似。巨噬细胞是先天免疫系统的重要细胞组成部分，是先天免疫和获得性免疫之间的联系，也是HIV/SIV感染的重要靶点。 我们认为，在HIV感染期间，不仅CD 4 T细胞，而且单核细胞/巨噬细胞也参与了艾滋病的发病机制和进展。 这是基于我们的初步数据，显示与对照未感染动物相比，SIV感染动物的单核细胞更新率较高。强烈认为感染猴淋巴结中组织巨噬细胞的大量破坏是单核细胞高周转的原因。更重要的是，在一项对四只SIV感染猴的小型队列的纵向研究中，显示早期高和持续单核细胞更新的动物是一个快速进展者，尽管与队列中的其他动物相比，T细胞活化水平，高病毒载量和CD 4计数相似，但死于艾滋病。单核细胞更新在艾滋病进展中很重要的观点得到了以下事实的有力支持：当所有死于艾滋病的慢性感染动物（经病理学诊断）或仍然存活的动物在注射BrdU后分析存活时间时，预测进展为艾滋病的唯一参数具有统计学显著性，即单核细胞更新高。我们的假设是SIV/HIV对组织巨噬细胞的进行性破坏是决定AIDS疾病进展的主要因素之一。这一假说的一个推论是，血液中单核细胞的高周转是组织巨噬细胞大量破坏的结果，可能是艾滋病疾病进展的预测因子。