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感染的人类和siv感染的猕猴的机会性感染。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。虽然关于这种普遍免疫激活的原因的明确机制尚未得到证实，但已经提出了一种微生物易位理论，认为粘膜屏障和粘膜免疫的破坏发生在CD4 T细胞耗竭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。然而，这种发病理论的因果关系尚未阐明，特别是因为并非所有CD4 T细胞水平低的感染者的进展都与艾滋病相似。该建议的目的是通过关注巨噬细胞的作用来检查HIV/ siv相关发病机制的早期阶段，这些发病机制可以解释微生物易位。巨噬细胞是先天免疫系统的重要组成部分，连接着从先天免疫到适应性免疫的转变，并且是HIV/SIV感染的宿主细胞靶点。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，这与艾滋病的进展直接相关，这支持了本提案中关注巨噬细胞的基本原理。在一只受感染的猴子的淋巴结中观察到组织巨噬细胞的大量破坏似乎有助于单核细胞的高周转率。此外，初步数据表明，最近从单核细胞分化的巨噬细胞的一个特定细胞亚群是SIV感染的主要目标。该申请的主要目的是利用SIV感染的非人灵长类动物模型来解决组织巨噬细胞在艾滋病发病机制中的作用。本研究的目的是确定导致系统性免疫激活的微生物易位是否是由于功能失调的巨噬细胞先天免疫功能的减弱。假设SIV感染对特异性巨噬细胞亚群的损伤会破坏先天免疫的第一道防线，从而导致消化道菌群突破粘膜屏障，促进全身免疫激活和艾滋病的发病机制。

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.