Monocyte/macrophages in the pathogenesis of AIDS in macaques

描述（由申请人提供）：在这项研究中，我们提出单核细胞/巨噬细胞可能在HIV感染期间严重参与了艾滋病的发病机制和进展。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明显的组织巨噬细胞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。因此，在这项研究中，我们建议用致病性SIV 251病毒感染8只恒河猴，以详细证明单核细胞周转量的变化是否真的能预测AIDS疾病的进展。此外，将研究单核细胞更新的机制。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（见初步数据）。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。 公共卫生相关性：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。在所提出的申请中，将在SIV/恒河猴动物模型中检查单核细胞/巨噬细胞谱系细胞在AIDS发病机制中的作用。我们认为，不仅CD 4 T细胞，而且单核细胞/巨噬细胞参与艾滋病的发病机制和发展过程中的艾滋病病毒感染。

DESCRIPTION (provided by applicant): In this study, we propose that the monocytes/macrophages may be heavily involved in the pathogenesis and progression to AIDS during HIV infection. Our preliminary data show a high monocyte turnover in SIV infected animals compared to control uninfected animals. Massive destruction of tissue macrophages evident in the 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. Therefore, in this study we propose to infect 8 rhesus macaques with pathogenic SIV251 virus to demonstrate in detail if changes in the magnitude of the monocyte turnover will in fact predict AIDS disease progression. Moreover, the mechanism of the monocyte turnover will be studied. 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 (see preliminary data). 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. PUBLIC HEALTH RELEVANCE: 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. In the proposed application, the role of monocyte/macrophage lineage cells in the pathogenesis of AIDS will be examined in the SIV/rhesus macaque animal model. 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.