Monocyte/macrophages in the pathogenesis of AIDS in macaques

描述(申请人提供)：在这项研究中，我们认为单核/巨噬细胞可能在HIV感染过程中与艾滋病的发病和进展密切相关。我们的初步数据显示，与未感染的对照动物相比，SIV感染动物的单核细胞周转率较高。在被感染的猴子的淋巴结中，明显的组织巨噬细胞的大量破坏被强烈地认为是单核细胞高周转率的原因。更重要的是，在对四只感染SIV的猴子进行的一小群纵向研究中，表现出早期高且持续的单核细胞转换率的动物是一个快速进展的动物，并死于艾滋病，尽管与队列中的其他动物相比，它们的T细胞激活水平、病毒载量和CD4计数相似。因此，在这项研究中，我们建议用致病的SIV251病毒感染8只恒河猴，以详细证明单核细胞周转率的变化是否确实可以预测艾滋病的进展。此外，还将对单核细胞周转的机制进行研究。单核细胞周转在艾滋病进展中的重要性这一观点得到了以下事实的有力支持：当对所有慢性感染的死于艾滋病(经病理诊断)的动物或仍然活着的动物分析BrdU注射后的存活时间时，具有统计学意义的唯一预测进展为艾滋病的参数是高单核细胞周转(见初步数据)。我们的假设是，SIV/HIV对组织巨噬细胞的渐进破坏是决定艾滋病疾病进展的主要因素之一。这一假设的一个推论是，血液中单核细胞的高周转率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指标。 公共卫生相关性：人们普遍认为，破坏CD4+T细胞是免疫缺陷的主要原因，表现为HIV-1感染者和SIV感染猕猴的机会性感染。然而，决定疾病进展速度的机制尚未阐明。并不是所有CD4细胞计数低的感染者的进展都与艾滋病相似。巨噬细胞是先天免疫系统的重要细胞成分，是连接先天免疫和获得性免疫的纽带，也是HIV/SIV感染的重要靶点。在拟议的应用中，将在SIV/恒河猴动物模型中检查单核/巨噬细胞系细胞在艾滋病发病机制中的作用。我们认为，在HIV感染过程中，不仅CD4T细胞参与了艾滋病的发生和发展，单核/巨噬细胞也参与了这一过程。

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.