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: 10701472
• 负责人: Ashish Arunkumar Sharma
• 金额: $ 36.01万
• 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/10701472
• 关键词: Address; Adolescence; Adult; Age; Anti-Inflammatory Agents; Bile Acids; Binding; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Maintenance; Cell physiology; Cells; Child; Childhood; Complex; DNA; Data; Emigrant; Environment; Epigenetic Process; Flow Cytometry; Frequencies; Genes; Genetic Transcription; HIV; HIV Infections; Homeostasis; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Immunologics; Immunology; Impairment; Interleukin-10; International Maternal Pediatric Adolescent AIDS Clinical Trials; Interruption; Knowledge; Life; Longitudinal cohort; Maintenance; Memory; Metabolic; Mission; Modeling; Molecular; Monitor; Nature; Neonatal; Output; Pathway interactions; Production; Proviruses; Regulatory T-Lymphocyte; Research; Research Personnel; SIV; Sampling; System; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Thymus Gland; Transforming Growth Factor beta; Translations; Viremia; Volatile Fatty Acids; age group; antiretroviral therapy; biobank; clinical trial protocol; cohort; cytokine; early childhood; effector T cell; efficacy evaluation; epigenetic profiling; exhaustion; high dimensionality; immune function; immunoregulation; integration site; interdisciplinary approach; interest; machine learning algorithm; metabolomics; microbial; novel; pathogen; pediatric human immunodeficiency virus; perinatal HIV; perinatal period; pressure; programs; stemness; synergism

ABSTRACT – Project 3 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 children living with HIV (CLWH) can be created. The knowledge gap we address in Project 3 is how the establishment and maintenance of HIV reservoirs are regulated by the neonatal and childhood immune system, with specific focus on host and bacterial metabolites, immunoregulatory cytokines, and thymic output. HIV persistence in adults is driven by recognizable metabolomic and microbial profiles that include metabolites modulating epigenetic changes in genes regulating innate/adaptive immune cell function and HIV latency. Studies in CLWH clearly demonstrate that the size of the HIV reservoir is variable with a high dynamic range. The hypothesis to be tested in Project 3 is that age- associated changes in HIV reservoir size and stability are driven by specific metabolites that influence CD4+ and CD8+ T cell function, cytokine production (e.g., IL-10 and TGF-β), and the level of HIV-infected recent thymic emigrants (RTEs). In Aim 1, we will quantify the contribution of thymic output and infected RTEs to changes in the size of the intact HIV reservoir. We will test the impact of the anti-inflammatory cytokine environment prevalent in younger age groups on thymic output and HIV reservoir seeding. In Aim 2, we will address how innate and adaptive cellular immune homeostasis and HIV-specific immune function are influenced by the host environment and thymic output using high-dimensional flow cytometry, cytokine analyses and transcriptional/epigenetic profiling on single cells. In Aim 3, we will decipher the impact of microbial/host metabolites on production of IL-10 and TGF-β, establishment and maintenance of HIV reservoirs, and innate/adaptive immune functions. Targeted metabolomics to quantify short chain fatty acids and primary/secondary bile acids will be used to define and validate relationships with levels of intact and translation competent HIV DNA. Finally, immunological, virological, and molecular data will be integrated, and machine learning algorithms will be used to develop models to predict the magnitude and features of HIV reservoirs. Longitudinal samples from two cohorts of CLWH (IMPAACT biorepository and EPIC4 study) allow us to monitor dynamics of HIV reservoirs across childhood. 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 expertise with cutting-edge systems immunology to deeply interrogate HIV. With multidisciplinary approaches, synergies across Projects and Cores, and our highly collaborative group of established and early-stage investigators, we are confident that Project 3 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-项目3 本计划项目申请的总体目标是全面了解 复杂的宿主-病原体相互作用对艾滋病毒宿主的播种和持久性至关重要，因此新的治愈方法 可以创建真正针对艾滋病毒携带者儿童(CLWH)独特免疫环境的战略。 我们在项目3中解决的知识差距是如何建立和维护艾滋病毒蓄水池 由新生儿和儿童免疫系统调节，特别关注宿主和细菌代谢物， 免疫调节细胞因子和胸腺输出。成年人中艾滋病毒的持续存在是由可识别的 代谢组学和微生物谱，包括调节基因调控表观遗传变化的代谢物 先天/获得性免疫细胞功能和艾滋病毒潜伏期。CLWH的研究清楚地表明， HIV储存库是可变的，具有高动态范围。在项目3中要检验的假设是年龄- HIV储备库大小和稳定性的相关变化是由影响CD4+的特定代谢物驱动的 和CD8+T细胞功能，细胞因子的产生(例如，IL-10和转化生长因子-β)，以及最近感染艾滋病毒的水平 胸腺移民(RTE)。在目标1中，我们将量化胸腺输出和受感染的rte对 完整的艾滋病毒储存库的大小发生了变化。我们将测试抗炎细胞因子的影响 在较年轻的年龄组中普遍存在的环境对胸腺输出和艾滋病毒储存库播种。在目标2中，我们将 阐述先天和适应性细胞免疫动态平衡和HIV特异性免疫功能是如何 用高维流式细胞术检测受宿主环境和胸腺输出影响的细胞因子 对单细胞进行分析和转录/表观遗传学分析。在目标3中，我们将破译 微生物/宿主代谢产物对IL-10和转化生长因子-β的产生及HIV的建立和维持 蓄水池和先天/适应性免疫功能。靶向代谢组学在短链脂肪酸定量中的应用 初级/次级胆汁酸将被用来定义和验证与完整和 翻译能力强的HIV DNA。最后，将整合免疫学、病毒学和分子数据，并 机器学习算法将被用来开发预测艾滋病毒的规模和特征的模型 水库。来自CLWH(IMPAACT生物仓库和EPIC4研究)两个队列的纵向样本允许 美国将监测儿童时期艾滋病毒宿主的动态。更好地了解艾滋病毒的脆弱性 先天免疫压力和适应性免疫压力将推动治疗慢性肝炎的知情方法。这个 拟议的研究建立在我们尖端系统免疫学专业知识的基础上，以深入询问艾滋病毒。 凭借多学科方法、跨项目和核心的协同效应，以及我们高度协作的 作为成熟的和早期的调查人员，我们相信项目3将导致重要的发现 关于儿童艾滋病毒蓄积物的免疫调节和免疫功能障碍。我们的使命是把 这些发现转化为临床试验方案，以推进治疗艾滋病毒儿童的研究。