Immune determinants of pediatric HIV/SIV reservoir establishment and maintenance

摘要-总体 新的围产期艾滋病毒感染仍在继续，大约每3-4分钟就有一例，每天400例，每天3000例。 每周都有对于感染艾滋病毒的儿童，抗逆转录病毒疗法大大降低了死亡率， 发病率;然而，如果停止ART，病毒反弹迅速加剧。艾滋病毒在一个潜伏的水库中持续存在， 可引起反弹病毒血症的CD 4 + T细胞是治愈的主要障碍。然而，仍然有一个 在如何管理艾滋病毒储存库的建立和维持方面存在重大知识差距 通过新生儿和儿童的免疫系统。本计划项目申请的总体目标是 全面了解对HIV宿主至关重要的复杂宿主-病原体相互作用 接种和持久性，使新的治疗策略真正针对独特的免疫环境， 可以创建CLWH。我们的中心假设是，宿主免疫环境在围产期 时期和整个儿童期和青春期，受宿主/微生物代谢产物和胸腺输出的影响， 决定了艾滋病毒特异性免疫的效力以及储存库建立和维持的性质。 为了验证这一假设，我们组建了一支由经验丰富的科学家和早期 来自埃默里医学院儿科和病理学系的研究人员（ESI）， 来自NIH、Kirby Institute和蒙特利尔大学的合作者。这项研究建立在 强大的现有合作产生了严格的基础研究，以支持每个项目 并在新的合作者之间建立联系。项目监督、沟通计划和指导 环境影响指数将通过行政核心进行协调。我们在项目1-3中提出了多组学实验 数据集中在生物信息学核心。我们计划的总体具体目标是：1） 研究IL-10、TGF-β和胸腺输出对免疫功能和储库建立的影响， 维持围产期HIV/SIV感染; 2）确定CD 8 + T细胞在储库建立中的作用 围产期HIV/SIV感染的维持; 3）产生定义宿主免疫的整合模型 HIV/SIV储库建立和维持的决定因素，并预测HIV/SIV储库的大小和性质。 在CLWH水库。这种对儿科免疫学的深入研究将使我们能够获得一些 如果每个项目都是单独进行的话。更好地了解艾滋病毒的脆弱性 先天性和适应性免疫压力的储存库将推动知情的方法来治愈CLWH。的 研究建议建立在我们团队的专业知识，丰富的资源，在医学院埃默里， 埃默里国家灵长类动物研究中心，埃默里艾滋病研究中心，并慷慨地获得 来自两个CLWH队列的生物标本。我们相信，这项计划将导致重要的发现。 关于儿科HIV储库和免疫功能障碍的免疫调节。我们的使命是 将这些发现转化为临床试验方案，以推动治愈艾滋病毒感染儿童的研究。

ABSTRACT - Overall New perinatal HIV infections continue, at a rate of about one every 3-4 minutes, 400 every day, and 3000 every week. For children living with HIV (CLWH), antiretroviral therapy (ART) greatly reduces mortality and morbidity; however, viral rebound quickly ensues if ART is stopped. HIV persistence in a latent reservoir in CD4+ T cells that can give rise to rebound viremia is the major barrier to a cure. However, there remains a significant knowledge gap regarding how the establishment and maintenance of HIV reservoirs are regulated by the neonatal and childhood immune system. The overall objective of this Program project application is to generate a comprehensive understanding of the complex host-pathogen interactions critical for HIV reservoir seeding and persistence such that novel cure strategies truly targeted for the unique immune environment of CLWH can be created. Our central hypothesis is that the host immune environment during the perinatal period and throughout childhood and adolescence, influenced by host/microbial metabolites and thymic output, determines the efficacy of HIV-specific immunity and the nature of reservoir establishment and maintenance. To test this hypothesis, we have compiled an outstanding team of experienced scientists and early-stage investigators (ESIs) from the Departments of Pediatrics and Pathology at Emory School of Medicine, with collaborators from the NIH, Kirby Institute, and the Université de Montréal. The research proposed builds upon the strong existing collaborations that generated the rigorous foundational research in support of each Project and develops links between new collaborators. Program oversight, communication plans, and mentoring of ESIs will be coordinated through the Administrative Core. We propose multiomic experiments in Projects 1-3 with data centralization in the Bioinformatics Core. The overall Specific Aims of our Program are: 1) To investigate the impact of IL-10, TGF-β, and thymic output on immune function and reservoir establishment and maintenance in perinatal HIV/SIV infection; 2) To determine the role of CD8+ T cells in reservoir establishment and maintenance in perinatal HIV/SIV infection; 3) To generate integrative models that define the host immune determinants of HIV/SIV reservoir establishment and maintenance and predict the size and nature of the HIV reservoir in CLWH. This deep dive into pediatric immunology will allow for insights to emerge that would not be possible if each Project were performed in isolation. A better understanding of the vulnerability of HIV reservoirs to innate and adaptive immune pressure will drive informed approaches to a cure for CLWH. The research proposed builds on our team’s expertise, the rich resources available at Emory School of Medicine, Emory National Primate Research Center, Emory Center for AIDS Research, and generous access to biospecimens from two cohorts of CLWH. We are confident that this Program will lead to important discoveries regarding immune regulation of the pediatric HIV reservoir and immune dysfunction. It is our mission to turn these discoveries into clinical trial protocols to advance research towards a cure for children with HIV.