Targeting Macrophage Reservoirs in the Macaque Model of Pediatric AIDS

儿科艾滋病猕猴模型中针对巨噬细胞库的研究

• 批准号: 8842376
• 负责人: Marcelo J Kuroda
• 金额: $ 22.82万
• 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: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8842376
• 关键词: AIDS/HIV problem; Achievement; Acquired Immunodeficiency Syndrome; Acute; Adult; Alendronate; Alveolar Macrophages; Animal Model; Anti-Retroviral Agents; Antibodies; Bacteriophages; CD4 Positive T Lymphocytes; Cells; Child; Childhood; Chronic Phase of Disease; DNA; Developed Countries; Developing Countries; Development; Disease; Disease Progression; Encapsulated; Exhibits; Foundations; Goals; HIV; HIV Infections; HIV-1; Highly Active Antiretroviral Therapy; Human; Infection; Injection of therapeutic agent; Intervention; Lead; Life; Liposomes; Lung; Macaca; Macaca mulatta; Maintenance; Measures; Modeling; Neonatal; Newborn Infant; Outcome; Pathogenesis; Pharmaceutical Preparations; Phase; Physiological; Plasma; Play; Population; Primates; RNA; Reporting; Rest; Role; SIV; Site; Specimen; Staging; Structure of parenchyma of lung; Terminal Disease; Tissues; Toxic effect; Vertical Disease Transmission; Viral; Viral Load result; Viremia; Virus; Virus Diseases; Work; antiretroviral therapy; base; cell type; in vivo; in vivo Model; interest; interstitial; lung basal segment; macrophage; memory CD4 T lymphocyte; monocyte; pediatric AIDS; prevent; public health relevance

DESCRIPTION (provided by applicant): Elimination of virus reservoirs that persist in HIV-infected children and adults despite long-term suppression of plasma viremia by traditional antiretroviral therapy (ART) is crucial for curing HIV infection. To identify and ultimately destro these latently infected virus reservoirs that promote virus rebound, it becomes important to first specifically identify the cells and tissue sites that harbor HIV during latency induced by ART. Our long-term goal is to inhibit or prevent the development of viral reservoir host cells that aris despite ART in HIV-infected children. The purpose of this R21/R33 proposal is to verify the contributions of CD4+ T cells and macrophages as reservoir cells in SIV-infected and ART-treated pediatric macaques. Our central hypothesis is that in SIV-infected newborn macaques where pathogenesis occurs more rapidly than in adults, tissue macro- phages also serve as major virus (SIV) reservoirs after infection. 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. We propose two aims in phase I (R21) of this application: Aim 1. To determine the contribution of CD4+ T cells to the virus reservoir in SIV-infected pediatric macaques undergoing effective ART. Our working hypothesis is that in vivo depletion of CD4+ cells in SIV- infected newborn macaques undergoing effective ART will directly demonstrate the proportion of CD4+ T cells (vs macrophages) that contribute to the SIV reservoir. We will use a well-established in vivo model via injection of anti-CD4 depleting antibody to remove CD4+ T cells in the SIV-infected macaques undergoing optimal ART. Aim 2. To determine the contribution of monocytes/macrophages to the virus reservoir in SIV-infected pediatric macaques undergoing effective ART. Our working hypothesis is that the in vivo depletion of monocyte/macrophages of the SIV-infected macaques undergoing effective ART will also demonstrate a contribution of macrophages (vs CD4+ T cells) to the SIV reservoir in the lung. We will use in vivo administration of liposome-encapsulated alendronate that temporarily depletes monocytes/macrophages in macaques. These results will ascertain if both CD4+ T cells and tissue macrophages, or either set of cells alone, develop and mature into reservoirs sites of SIV during effective ART. Tissue specimens will be examined in fine detail to measure viral levels (RNA and DNA) as well as identify specific sites and subset markers of reservoir cells infected with SIV during ART. This will set the foundation for aim 3 of phase II (R33) to corroborate if viral reservoirs were eliminated or drastically reduced by discontinuation of ART. Aim 3. To determine if in vivo depletion of CD4+ T cells and/or monocyte/macrophages prevents virus rebound after discontinuation of ART in SIV-infected newborn macaques. Our working hypothesis is that both CD4+ T cells and macrophages contribute to SIV reservoirs and that elimination of either or both cell populations followed by discontinuation of ART will lead to maintenance of low or absent viral loads. If virus rebound occurs, it will help to corroborate the remaining or alternate sites of the virus reservoirs. This study will contribute to developing rational intervention strategies to reduce or cure AIDS in HIV-infected children.

描述（由申请人提供）：尽管通过传统抗逆转录病毒疗法（ART）长期抑制血浆病毒血症，但消除HIV感染儿童和成人中持续存在的病毒储库对于治愈HIV感染至关重要。为了识别并最终摧毁这些潜伏感染的病毒库，促进病毒反弹，它变得很重要，首先明确确定的细胞和组织网站，窝藏艾滋病毒在潜伏期诱导ART。我们的长期目标是抑制或防止病毒库宿主细胞的发展，尽管ART在艾滋病毒感染的儿童。该R21/R33提案的目的是验证CD 4 + T细胞和巨噬细胞作为SIV感染和ART治疗的小儿猕猴中的储库细胞的贡献。我们的中心假设是，在SIV感染的新生猕猴中，发病率比成年猕猴更快，组织巨噬细胞也是感染后的主要病毒（SIV）储存库。我们假设的基本原理是：（i）新生猕猴的SIV感染与在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，可以更详细地检查SIV的储存部位 并且在比HIV感染者更受控的实验条件下进行。我们在本申请的第一阶段（R21）提出了两个目标：目标1。为了确定在接受有效ART的SIV感染的小儿猕猴中CD 4 + T细胞对病毒库的贡献，我们的工作假设是，在接受有效ART的SIV感染的新生猕猴中，体内CD 4+细胞的耗竭将直接证明对SIV库有贡献的CD 4 + T细胞（与巨噬细胞）的比例。我们将使用一个良好建立的体内模型，通过注射抗CD 4耗竭抗体，以消除接受最佳ART的SIV感染猕猴中的CD 4 + T细胞。为了确定单核细胞/巨噬细胞对接受有效ART的SIV感染的儿童猕猴中病毒储库的贡献。我们的工作假设是，接受有效ART的SIV感染的猕猴的单核细胞/巨噬细胞的体内耗竭也将证明巨噬细胞（vs CD 4 + T细胞）对肺中SIV储库的贡献。我们将使用体内给药的脂质体包封的阿仑膦酸钠，暂时消耗猕猴的单核细胞/巨噬细胞。这些结果将确定是否CD 4 + T细胞和组织巨噬细胞，或单独的任一组细胞，在有效的抗逆转录病毒治疗过程中，SIV会发展并成熟为SIV的储存库。（RNA和DNA）以及确定ART期间SIV感染的储库细胞的特异性位点和亚群标志物。这将为II期（R33）目标3奠定基础。以证实是否通过停止抗逆转录病毒治疗消除或大幅减少了病毒储库。目的3.确定体内清除CD 4 + T细胞和/或单核细胞/巨噬细胞是否可预防SIV感染的新生猕猴停止ART后病毒反弹。我们的工作假设是，CD 4 + T细胞和巨噬细胞都有助于SIV储库，并且在停止ART后消除其中一个或两个细胞群将导致维持低或无病毒载量。如果发生病毒反弹，这将有助于证实病毒宿主的剩余或替代位点。本研究将有助于制定合理的干预策略，以减少或治愈艾滋病病毒感染儿童。