Role of Macrophages in Lung Disease Pathogenesis of Pediatric AIDS

描述(由申请人提供)：艾滋病毒引起慢性肺部疾病(CLD)的机制尚不清楚，慢性肺部疾病是艾滋病毒感染儿童最常见的并发症。尽管通过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，在促进炎症和慢性阻塞性肺疾病的抗逆转录病毒治疗过程中，特别识别携带艾滋病毒的细胞是很重要的。我们的长期目标是抑制或逆转慢性阻塞性肺疾病的发展，尽管艾滋病病毒感染的儿童出现了这种情况。作为第一步，这项建议的目的是验证巨噬细胞，除CD4T细胞外，在接受抗逆转录病毒治疗后，是否作为SIV感染新生儿肺内的病毒库细胞。我们的中心假设是，组织巨噬细胞是主要病毒(SIV)的储存库，在感染SIV的早期，以及在SIV感染的新生儿猕猴组织中从短期巨噬细胞向长期巨噬细胞的过渡期间，SIV感染的猕猴比成年猕猴发展得更快。我们假设的基本原理是：(I)新生儿猕猴中的SIV感染与在感染艾滋病毒的儿童中观察到的疾病快速发展相平行，(Ii)在灵长类动物模型中，SIV的储存部位可能是 与艾滋病毒感染者相比，在更详细的实验条件下进行了更详细的检查。为了充分了解巨噬细胞在肺中的作用，研究肺组织变得至关重要，而不是依赖只含有AM的BAL标本这些研究将确定经ART治疗的SIV感染猕猴中的病毒宿主细胞储存库，这将指导未来开发新的艾滋病毒感染儿童治疗策略。目的：1.明确SIV感染的新生猕猴在感染后不同时间开始抗逆转录病毒治疗后肺组织损伤的程度。我们的工作假设是，在SIV感染后早期，感染SIV的新生儿猕猴肺组织中的病毒感染将在单核/巨噬细胞系细胞中更高，并将与组织损伤的程度相关。这是基于初步数据显示，感染SIV的新生儿组织巨噬细胞中病毒感染率更早和更高。我们还假设，在新生儿感染后较早启动ART将比较晚启动ART更能减少SIV感染的巨噬细胞储存库，并且病毒储存库的大小将决定肺部炎症的严重程度。目的2.确定SIV感染的新生猕猴在接受有效的抗逆转录病毒治疗后，肺单核/巨噬细胞或CD4T细胞的耗竭是否能减少肺部的慢性炎症。我们的工作假设是，在接受有效的ART治疗的SIV感染的新生儿猕猴体内，CD4细胞(抗CD4)的耗竭将直接证明CD4T细胞(VS巨噬细胞)在肺组织损伤发病机制中的作用。相反，在接受有效的抗逆转录病毒治疗的SIV感染的新生猕猴中，肺泡巨噬细胞(脂质体-阿伦磷酸钠)在体内的耗竭将决定巨噬细胞(相对于CD4T细胞)在肺部发病中的作用。

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.