Macrophages in the pathogenesis of AIDS

描述(由申请人提供)：CD4+T细胞的破坏被认为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。随后，HIV/SIV相关的慢性免疫激活也成为HIV发病机制的重要解释。虽然这种全身免疫激活的原因还没有明确的机制，但已经提出了微生物易位理论，认为粘膜屏障和粘膜免疫的破坏是在CD4T细胞耗尽导致全身暴露于粘膜微生物病原体及其产物(如内毒素)之后发生的。然而，这一发病机制理论的原因和结果尚未阐明，特别是因为并不是所有CD4T细胞水平低的感染者的进展与艾滋病相似。这项建议的目的是通过关注巨噬细胞的作用来检查HIV/SIV相关致病的早期阶段，这可能是微生物易位的原因。巨噬细胞是先天免疫系统的重要组成部分，是先天免疫向获得性免疫过渡的纽带，是HIV/SIV感染的宿主细胞靶点。为了支持这一建议中关注巨噬细胞的理论，我们最近的数据显示，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，这与进展为艾滋病直接相关。在感染的猴子的淋巴结中观察到的组织巨噬细胞的大量破坏似乎是导致单核细胞转化率高的原因之一。此外，初步数据表明，来自单核细胞的最近分化的巨噬细胞的特定细胞亚群是SIV感染的主要目标。拟议应用的主要目标是利用SIV感染的非人类灵长类动物模型来研究组织巨噬细胞在艾滋病发病机制中的作用。这项建议的目的是确定导致全身免疫激活的微生物易位是否是由于功能失调的巨噬细胞的天然免疫功能减弱所致。假设SIV感染对特定的巨噬细胞亚群的破坏将破坏先天免疫的第一道防线，因此，消化道的细菌菌群将突破粘膜屏障，促进全身免疫激活和艾滋病的发病。 公共卫生相关性：了解艾滋病在艾滋病毒感染中的发病机制的研究主要集中在T细胞上。这是因为CD4+T细胞是HIV感染的主要目标，而这些细胞的丧失与艾滋病相关。虽然毫无疑问，CD4+缺乏在艾滋病的发病机制中发挥了重要作用，但我们对艾滋病毒感染对先天性免疫的影响，特别是对单核/巨噬细胞生物学的影响，并没有以同样的速度取得进展。我们推测，在CD4+T细胞水平下降的同时，艾滋病毒也会影响单核/巨噬细胞系细胞，这可能会对艾滋病毒感染发展为艾滋病产生更深远的影响。我们假设，尽管巨噬细胞的绝对细胞数保持不变(即功能的丧失而不是细胞的数目)，但巨噬细胞的固有屏障功能的丧失仍会发生。我们的研究表明，在SIV感染过程中(通过细胞的高周转率)，骨髓付出了巨大的努力来维持所需数量的循环单核细胞，以应对组织巨噬细胞的大规模破坏。这一观察结果支持了单核/巨噬细胞系在维持日常免疫平衡中的关键作用。在SIV感染期间，骨髓为供应和维持单核/巨噬细胞水平而进行的高周转率也解释了为什么免疫系统的这一臂以前没有报道过损伤(而CD4+T细胞损伤更明显)。拟议应用的主要目标是利用SIV感染的非人类灵长类动物模型来研究组织巨噬细胞在艾滋病发病机制中的作用。

DESCRIPTION (provided by applicant): Destruction of CD4+ T cells is considered the primary cause of immunodeficiency manifested by opportunistic infections in HIV-1-infected humans as well as in SIV-infected macaques. Subsequently, HIV/SIV-associated chronic immune activation also has emerged as an important explanation for HIV pathogenesis. Although a clearly-defined mechanism about the cause of this general immune activation has yet to be demonstrated, a microbial translocation theory has been proposed whereby breakdown of the mucosal barrier and mucosal immunity is thought to occur after with depletion of CD4 T cells resulting in systemic exposure to mucosal microbial pathogens and their products (e.g. endotoxin). The cause and effect of this theory of pathogenesis, however, has yet to be elucidated, especially since not all infected individuals with low CD4 T cell levels progress similarly to AIDS. The purpose of this proposal is to examine earlier stages of HIV/SIV-associated pathogenesis that could account for microbial translocation by focusing on the role of macrophages. Macrophages are important components of the innate immune system, link the transition from innate to adaptive immunity, and serve as host cell targets of HIV/SIV infection. In support of the rationale to focus on macrophages in this proposal, our recent data showed a high monocyte turnover in SIV-infected animals compared to control uninfected animals that directly correlated with progression to AIDS. Massive destruction of tissue macrophages observed in the lymph nodes of an infected monkey appeared to contribute to a high monocyte turnover rate. Furthermore, preliminary data indicated that a specific cell subset of recently differentiated macrophages from monocytes were the main target of SIV infection. The main goal of the proposed application is to address the role of tissue macrophages in the pathogenesis of AIDS using the non-human primate model of SIV infection. The goal of this proposal is to determine if microbial translocation leading to systemic immune activation is due to faltering innate immunity by dysfunctional macrophages. The hypothesis is that damage to specific macrophage cell subsets by SIV infection will compromise the first line of defense in innate immunity, and as a consequence, the bacterial flora of the digestive tract will break through the mucosal barrier to contribute to systemic immune activation and pathogenesis of AIDS. PUBLIC HEALTH RELEVANCE: Studies to understand the pathogenesis of AIDS in HIV infection have focused primarily on T cells. This is because CD4+T cells are a major target of HIV infection, and the loss of these cells correlates with AIDS. While there is no doubt that CD4+ deficiency plays a major role in the pathogenesis of AIDS, our understanding about the impact of HIV infection on innate immunity in general, and on the biology of monocyte/macrophages in particular, has not progressed at the same pace. We hypothesize that in conjunction with declining levels of CD4+ T cells, HIV also affects monocyte/macrophage lineage cells that may have an even more profound impact on the progression of HIV infection to AIDS. We hypothesize that the loss of the innate barrier function of macrophages occurs despite maintenance of absolute cell numbers (i.e. loss of function rather than cell number). Our studies demonstrated that enormous effort is given by the bone marrow to maintain the needed numbers of circulating monocytes over the course of SIV infection (via high turnover of cells) in response to the massive destruction of tissue macrophages. This observation supports a crucial role of the monocyte/macrophage cell lineage in the maintenance of daily immunological homeostasis. The high turnover rate by the bone marrow to supply and maintain monocyte/macrophages levels during SIV infection could also explain why damage in this arm of the immune system was not previously reported (whereas CD4+ T cell damage was more readily apparent). The main goal of the proposed application is to address the role of tissue macrophages in the pathogenesis of AIDS using the non-human primate model of SIV infection.