Role of Macrophages in Lung Disease Pathogenesis of Pediatric AIDS

巨噬细胞在儿童艾滋病肺部疾病发病机制中的作用

• 批准号: 8790574
• 负责人: Marcelo J Kuroda
• 金额: $ 85.48万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-08 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8790574
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Adult; Alendronate; Alveolar Macrophages; Antibodies; CD4 Positive T Lymphocytes; Cell Lineage; Cells; Child; Childhood; Chronic; Chronic lung disease; Complication; Data; Developed Countries; Developing Countries; Development; Disease; Disease Progression; Encapsulated; Exhibits; Future; Goals; HIV; HIV-1; Highly Active Antiretroviral Therapy; Human; Infection; Inflammation; Life; Liposomes; Lung; Lung Inflammation; Lung diseases; Macaca; Macaca mulatta; Modeling; Neonatal; Newborn Infant; Outcome; Pathogenesis; Physiological; Plasma; Play; Primates; Public Health; Reporting; Rest; Role; SIV; Severities; Site; Specimen; Staging; Structure of parenchyma of lung; Terminal Disease; Time; Tissues; Vertical Disease Transmission; Viral; Viremia; Virus; Virus Diseases; Work; antiretroviral therapy; base; defined contribution; in vivo; interstitial; macrophage; memory CD4 T lymphocyte; monocyte; neonate; nonhuman primate; novel strategies; novel therapeutics; pediatric AIDS; public health relevance

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.

描述（由申请人提供）：人们对 HIV 引起慢性肺病（CLD）的机制知之甚少，慢性肺病是 HIV 感染儿童最常见的并发症。尽管传统抗逆转录病毒疗法（ART）长期抑制血浆病毒血症，但病毒储存库仍然存在于肺部。因此，在 ART 期间明确识别携带 HIV 并促进炎症和慢性肺病 (CLD) 的细胞非常重要。我们的长期目标是抑制或逆转感染艾滋病毒的儿童在接受抗逆转录病毒治疗后仍出现慢性肺病的情况。作为第一步，该提案的目的是验证除 CD4+ T 细胞外，巨噬细胞在 ART 后感染 SIV 的新生儿的肺部中充当病毒储存细胞。我们的中心假设是，组织巨噬细胞是感染后早期以及感染 SIV 的新生猕猴组织中从短命巨噬细胞向长寿巨噬细胞转变期间的主要病毒 (SIV) 储存库，这些新生猕猴的疾病发展速度比成年猕猴更快。我们假设的基本原理是：(i) 新生猕猴中的 SIV 感染与 HIV 感染儿童中观察到的疾病快速进展是平行的，(ii) 在灵长类动物模型中，SIV 的储存位点可以是 与艾滋病毒感染者相比，该研究在更受控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部的作用，有必要研究肺组织，而不是依赖于仅含有 AM 的 BAL 样本。这些研究将确定经 ART 治疗的 SIV 感染猕猴体内的病毒宿主细胞储库，这将指导未来针对 HIV 感染儿童开发新的治疗策略。目的是： 目标 1. 确定感染 SIV 的新生猕猴在感染后不同时间开始 ART 后肺组织损伤的程度。我们的工作假设是，受感染的新生猕猴肺部的病毒感染在 SIV 感染后早期的单核细胞/巨噬细胞谱系细胞中会更高，并且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的病毒感染率较早且较高。我们还假设，新生儿感染后较早开始 ART 会比较晚开始 ART 更能减少 SIV 感染的巨噬细胞储库，并且病毒储库的大小将决定肺部炎症的严重程度。目标 2. 确定接受有效 ART 的感染 SIV 的新生猕猴中肺单核细胞/巨噬细胞或 CD4+ T 细胞的消耗是否可以减少肺部慢性炎症。我们的工作假设是，接受有效 ART 的感染 SIV 的新生猕猴体内 CD4+ 细胞（抗 CD4）的消耗将直接证明 CD4+ T 细胞（相对于巨噬细胞）在肺组织损伤发病机制中的作用。相反，接受有效 ART 的 SIV 感染新生猕猴肺部肺泡巨噬细胞（脂质体阿仑膦酸盐）的体内耗竭将决定巨噬细胞（相对于 CD4+ T 细胞）对肺部发病机制的贡献。