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）：艾滋病毒引起慢性肺部病（CLD）的机制，这是艾滋病毒感染儿童中最常见的并发症，知之甚少。尽管传统的抗逆转录病毒疗法（ART）对血浆病毒血症（ART）长期抑制，但病毒储层仍在肺部持续存在。因此，重要的是要在促进炎症和CLD的艺术期间专门鉴定细胞帽子伴有艾滋病毒。我们的长期目标是抑制或逆转CLD的发展，尽管艾滋病毒感染了艾滋病毒的儿童。作为第一步，该提案的目的是验证巨噬细胞除了CD4+ T细胞外，还可以作为ART后SIV感染的新生儿肺中的病毒储层细胞。我们的中心假设是，组织巨噬细胞是一种主要病毒（SIV）储层，在感染后以及从短暂寿命到长寿的巨噬细胞过渡期间，SIV感染的新生儿猕猴的组织中，它们比成年人更快。我们假设的理由是（i）新生猕猴中的SIV感染与HIV感染的儿童中观察到的快速疾病进展，以及（ii）在灵长类动物模型中，SIV的储层位点可以是 比在受HIV感染的人类中进行的细节和更受控的实验条件进行检查。为了充分了解巨噬细胞在肺中的作用，研究肺组织至关重要，而不是依靠仅包含AM的BAL标本。这些研究将在经过艺术治疗的SIV感染猕猴中鉴定病毒宿主细胞储存剂，这些猕猴将指导未来的HIV感染儿童治疗策略的发展。目的是：目标1。定义在感染后在不同时间发起的ART后，SIV感染的新生儿猕猴的肺组织损伤的幅度。我们的工作假设是，在SIV感染后，在单核细胞/巨噬细胞谱系中，单核细胞/巨噬细胞细胞中感染新生儿猕猴的病毒感染将更高，并且与组织损伤的幅度相关。这基于显示SIV感染的新生儿组织巨噬细胞中早期和更高病毒感染率的初步数据。我们还假设，在新生儿感染后，早期的艺术开始将减少SIV感染的巨噬细胞储层的库，而不是以后的ART启动，并且病毒储层的大小将决定肺部炎症的严重程度。目的2。确定在SIV感染的新出生的猕猴中肺单核细胞/巨噬细胞或CD4+ T细胞的耗竭是否会减少肺中的慢性炎症。我们的工作假设是，在经历有效ART的SIV感染的新生儿猕猴中，CD4+细胞的体内耗竭将直接证明CD4+ T细胞（VS巨噬细胞）在肺组织损伤的发病机理中的贡献。相反，SIV感染的新生儿猕猴的肺泡巨噬细胞（脂质体 - 阿内膦酸）的体内耗竭将定义巨噬细胞（VS. CD4+ T细胞）对肺病发病的贡献。