Immune determinants of pediatric HIV/SIV reservoir establishment and maintenance

儿科 HIV/SIV 病毒库建立和维持的免疫决定因素

• 批准号: 10701467
• 负责人: Ann M Chahroudi
• 金额: $ 156.37万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701467
• 关键词: Acquired Immunodeficiency Syndrome; Adaptive Immune System; Address; Adolescence; Antiviral Response; Binding; Bioinformatics; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Child; Childhood; Collaborations; Communication; Complex; Data; Development; Disease; Environment; Experimental Designs; Future; Goals; HIV; HIV Infections; Immune; Immune System Diseases; Immune system; Immunity; Immunology; In Vitro; Infection; Innate Immune System; Integration Host Factors; Interleukin-10; Investigation; Knowledge; Link; Maintenance; Mentors; Metabolic; Mission; Modeling; Morbidity - disease rate; Nature; Neonatal; Output; Pathology; Pathway interactions; Perinatal Infection; Pre-Clinical Model; Primates; Research; Research Personnel; Resources; Role; SIV; Scientist; System; Testing; Thymus Gland; Tissues; Transforming Growth Factor beta; United States National Institutes of Health; Viremia; Virus; Virus Latency; antiretroviral therapy; clinical trial protocol; cohort; curative treatments; efficacy evaluation; experience; experimental study; high dimensionality; immune function; immunoregulation; in vivo; insight; medical schools; microbial; mortality; multidisciplinary; multiple omics; novel; novel therapeutics; pathogen; pediatric department; pediatric human immunodeficiency virus; perinatal HIV; perinatal period; pressure; programs; single cell technology; synergism; tool development; viral rebound; virus host interaction

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.

摘要 - 总体 新的围产期 HIV 感染仍在继续，大约每 3-4 分钟就有 1 例、每天 400 例、3000 例 对于感染艾滋病毒的儿童 (CLWH)，抗逆转录病毒治疗 (ART) 大大降低了死亡率并降低了死亡率。 发病率；然而，如果停止抗逆转录病毒治疗，艾滋病毒在潜伏病毒库中持续存在，病毒很快就会反弹。 CD4+ T 细胞的升高会导致病毒血症反弹，这是治愈的主要障碍。 关于如何监管​​艾滋病毒储存库的建立和维护存在重大知识差距 该计划项目应用的总体目标是 全面了解对艾滋病毒储存库至关重要的复杂宿主-病原体相互作用 播种和持久性，使新的治疗策略真正针对独特的免疫环境 我们的中心假设是围产期的宿主免疫环境。 整个时期以及儿童期和青春期，受宿主/微生物代谢物和胸腺输出的影响， 决定了 HIV 特异性免疫的功效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阶段的科学家组成的优秀团队 来自埃默里医学院儿科和病理学系的研究人员 (ESI) 来自美国国立卫生研究院、柯比研究所和蒙特利尔大学的合作者提出的研究建立在这一基础上。 现有的强有力的合作产生了严格的基础研究来支持每个项目 并建立新合作者之间的联系、项目监督、沟通计划和指导。 ESI 将通过管理核心进行协调，我们建议在项目 1-3 中进行多组学实验。 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 围产期 HIV/SIV 感染的维持；2) 确定 CD8+ T 细胞在储存库建立中的作用 和维持围产期 HIV/SIV 感染；3) 生成定义宿主免疫的综合模型 HIV/SIV 储存库建立和维持的决定因素，并预测 HIV 的大小和性质 CLWH 中的储库对儿科免疫学的深入研究将带来一些原本不可能的见解。 如果每个项目单独进行，就有可能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治疗 CLWH 的明智方法。 拟议的研究建立在我们团队的专业知识和埃默里医学院丰富的资源的基础上， 埃默里国家灵长类动物研究中心、埃默里艾滋病研究中心以及慷慨的访问权 我们相信该计划将带来重要的发现。 关于儿童艾滋病毒储存库的免疫调节和免疫功能障碍是我们的使命。 这些发现纳入临床试验方案，以推进治疗艾滋病毒儿童的研究。