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病（CLD）的机制，艾滋病毒感染的儿童最常见的并发症，知之甚少。尽管传统的抗逆转录病毒治疗（ART）可以长期抑制血浆病毒血症，但病毒库仍存在于肺中。因此，重要的是要明确识别在ART期间携带HIV的细胞，这些细胞促进炎症和CLD。我们的长期目标是抑制或逆转HIV感染儿童在ART治疗后出现的CLD的发展。作为第一步，该提案的目的是验证巨噬细胞，除了CD 4 + T细胞，我们的中心假设是，组织巨噬细胞是感染后非常早期的主要病毒（SIV）储库，以及在SIV组织中从短寿命到长寿命的巨噬细胞的过渡期间，被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）新生猕猴中的SIV感染与HIV感染儿童中观察到的疾病快速进展平行，（ii）在灵长类动物模型中，SIV的储存库部位可能是 在比HIV感染者更精细的细节和更受控的实验条件下进行了检查。为了充分了解巨噬细胞在肺中的作用，研究肺组织而不是依赖于仅含有AM的BAL标本变得至关重要。这些研究将确定ART治疗的SIV感染猕猴中的病毒宿主细胞库，这将指导未来开发HIV感染儿童的新治疗策略。目标是：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，在感染的新生猕猴的ung中的病毒感染将在SIV感染后早期在单核细胞/巨噬细胞谱系细胞中更高，并且将与组织损伤的程度相关。这是基于初步数据显示SIV感染新生儿的组织巨噬细胞中的病毒感染率更早和更高。我们还假设，在新生儿感染后较早开始ART将减少SIV感染的巨噬细胞储库的池比晚开始ART，并且病毒储库的大小将决定肺部炎症的严重程度。目标二。确定在接受有效ART的SIV感染的新生猕猴中，肺单核细胞/巨噬细胞或CD 4 + T细胞的耗竭是否减少肺中的慢性炎症。我们的工作假设是，在体内消耗的CD 4+细胞（抗CD 4）在SIV感染的新生猕猴进行有效的ART将直接证明CD 4 + T细胞（相对于巨噬细胞）在肺组织损伤的发病机制的贡献。相反，在体内消耗肺泡巨噬细胞（脂质体-阿仑膦酸钠）的SIV感染的新生猕猴的肺进行有效的ART将定义的贡献巨噬细胞（相对于CD 4 + T细胞）的肺发病机制。