Role of Macrophages in Lung Disease Pathogenesis of Pediatric AIDS

描述（由申请人提供）：艾滋病毒导致慢性肺部疾病（CLD）的机制，这是艾滋病毒感染儿童最常见的并发症，目前尚不清楚。尽管传统的抗逆转录病毒疗法（ART）长期抑制血浆病毒血症，但病毒库仍然存在于肺部。因此，在抗逆转录病毒治疗期间特异性鉴定携带HIV的细胞促进炎症和CLD是很重要的。我们的长期目标是抑制或逆转艾滋病毒感染儿童在抗逆转录病毒治疗后出现的CLD的发展。作为第一步，本提案的目的是验证巨噬细胞，除了CD4+ T细胞外，在抗逆转录病毒治疗后SIV感染新生儿的肺中充当病毒库细胞。我们的中心假设是，在感染SIV的新生猕猴的组织中，组织巨噬细胞在感染后的早期以及从短寿命到长寿命的巨噬细胞转变过程中是一个主要的病毒（SIV）储存库，而SIV感染的新生猕猴比成年猕猴发病更快。我们假设的基本原理是：(i)新生猕猴的SIV感染与hiv感染儿童的快速疾病进展相似，（ii）在灵长类动物模型中，SIV的储存库位点可以是

DESCRIPTION (provided by applicant): The mechanisms by which HIV causes chronic lung disease (CLD), the most common complication in HIV- infected children, are poorly understood. Virus reservoirs persist in the lung despite long-term suppression of plasma viremia by traditional antiretroviral therapy (ART). Thus, it is important to specifically identify the cells hat harbor HIV during ART that promote inflammation and CLD. Our long-term goal is to inhibit or reverse development of CLD that arises despite ART in HIV-infected children. As a first step, the purpose of this proposal is to verify that macrophages, in addition to CD4+ T cells, serve as virus reservoir cells in the lung of SIV- infected newborns following ART. Our central hypothesis is that tissue macrophages are a major virus (SIV) reservoir very early after infection as well as during the transition from short-lived to longer-lived macrophages in tissues of SIV-infected newborn macaques that develop more rapid disease than adults. The rationale for our hypothesis is that (i) SIV infections in newborn macaques parallel the rapid disease progression observed in HIV-infected children, and (ii) in the primate model, the reservoir sites of SIV can be examined in finer detail and under more controlled experimental conditions than in HIV-infected humans. To fully understand the role of macrophages in the lung it becomes essential to study lung tissue rather than rely on BAL specimens that only contain AM. These studies will identify virus host cell reservoirs in ART-treated SIV-infected macaques that will guide future development of novel therapeutic strategies in HIV-infected children. The aims are: Aim 1. To define the magnitude of lung tissue damage of SIV-infected newborn macaques following ART initiated at different times post infection. Our working hypothesis is that virus infection in the ung of infected newborn macaques will be higher in monocyte/macrophage lineage cells early after SIV infection and will correlate with the magnitude of tissue damage. This is based on preliminary data showing earlier and higher virus infection rate in tissue macrophages of SIV-infected neonates. We also hypothesize that earlier initiation of ART after infection in neonates will decrease the pool of SIV-infected macrophage reservoirs more than later initiation of ART and that the size of the virus reservoir will dictate the severity of lung inflammation. Aim 2. To determine if depletion of lung monocyte/macrophages or CD4+ T cells in SIV-infected new- born macaques undergoing effective ART reduces chronic inflammation in the lung. Our working hypothesis is that in vivo depletion of CD4+ cells (anti-CD4) in SIV-infected newborn macaques undergoing effective ART will directly demonstrate the contribution of CD4+ T cells (vs macrophages) in the pathogenesis of the lung tissue damage. Conversely, the in vivo depletion of alveolar macrophages (liposome-alendronate) of the lung of the SIV-infected newborn macaques undergoing effective ART will define the contribution of macrophages (vs. CD4+ T cells) to the lung pathogenesis.