Macrophages in the pathogenesis of AIDS

描述（由申请方提供）：CD 4 + T细胞的破坏被认为是HIV-1感染的人以及SIV感染的猕猴中表现为机会性感染的免疫缺陷的主要原因。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。虽然关于这种一般免疫激活的原因的明确定义的机制尚未得到证实，但已经提出了微生物易位理论，其中认为粘膜屏障和粘膜免疫的破坏发生在CD 4 T细胞耗尽之后，导致全身暴露于粘膜微生物病原体及其产物（例如内毒素）。然而，这一发病机理理论的原因和影响尚未阐明，特别是因为并非所有CD 4 T细胞水平低的感染个体的进展与艾滋病相似。本提案的目的是研究HIV/SIV相关发病机制的早期阶段，通过关注巨噬细胞的作用，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，连接从先天免疫到适应性免疫的转变，并作为HIV/SIV感染的宿主细胞靶点。为了支持在这项提议中关注巨噬细胞的基本原理，我们最近的数据显示，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，这与艾滋病的进展直接相关。在感染猴淋巴结中观察到的组织巨噬细胞的大量破坏似乎有助于高单核细胞更新率。此外，初步数据表明，最近分化的单核细胞巨噬细胞的特定细胞亚群是SIV感染的主要目标。 该拟议应用的主要目标是使用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。本提案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导致的先天免疫功能减退。该假说认为，SIV感染对特定巨噬细胞亚群的损伤将危及先天免疫的第一道防线，因此，消化道的细菌植物群将突破粘膜屏障，有助于全身免疫激活和AIDS的发病。

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.