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

基本信息

批准号：
10701470
负责人：
Ann M Chahroudi
金额：
$ 54.44万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
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/10701470
关键词：
Address Adolescence Adult Anti-Inflammatory Agents Antigen Presentation Binding CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell Proliferation Cells Child Childhood Complex Data Emigrant Environment Event HIV HIV Infections IL10 gene Immune Immune System Diseases Immune response Immune system Immunity Immunology Immunosuppression Impairment Infant Infection Inflammatory Interleukin-10 Interruption Knowledge Lead Life Macaca Macaca mulatta Maintenance Mediating Mission Modeling Monoclonal Antibodies Morbidity - disease rate Nature Neonatal Output Pathway interactions Plasma Regulatory T-Lymphocyte Research Research Personnel Role SIV Sampling Signal Pathway Signal Transduction Stimulus System T cell response TGF Beta Signaling Pathway Testing Thymus Gland Time Transforming Growth Factor beta Viral Viral reservoir Viremia Virus antiretroviral therapy antiviral immunity biobank clinical trial protocol cytokine effector T cell efficacy evaluation genetic signature immune function immunoregulation improved in vivo infant infection interdisciplinary approach lymph nodes memory CD4 T lymphocyte microbial mortality multiple omics neonatal immune system neonatal period novel pathogen pediatric human immunodeficiency virus perinatal HIV perinatal period pressure programs simian human immunodeficiency virus stemness synergism viral rebound

项目摘要

ABSTRACT – Project 1 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 1 is how the establishment and maintenance of HIV reservoirs are regulated by the neonatal and childhood immune system, with specific focus on the role of IL-10 and TGF-β on innate and adaptive immune function, thymic output, survival of infected cells, and virus rebound. Multiple features of the early life immune environment differ from that of adults, including the active thymus and the tolerogenic/regulatory bias, with prominent T helper 2 and regulatory CD4+ T cells. The anti-inflammatory cytokines IL-10 and TGF-β are increased in infants and IL-10 is known to suppress antigen presentation, T cell effector function, and cell proliferation, while promoting survival of central memory CD4+ T cells. We have shown that lymph node CD4+ T cells from a subset of SHIV-infected infant rhesus macaques (RMs) that controlled viremia after analytical treatment interruption (ATI) were notable for an anti-IL-10 gene signature. The hypothesis to be tested in Project 1 is that IL-10 and TGF-β influence the magnitude of the HIV reservoir in infants and viral rebound post-ATI, while targeted modulation of IL-10/TGF-β signaling pathways will impair reservoir persistence and boost the immune responses that lead to post-ATI viral control. In Aim 1, we will evaluate how the cytokine milieu in infants impacts intact reservoir size, viral rebound, and antiviral immunity. In Aim 2, we will perform IL-10 blockade using an anti-IL-10 monoclonal antibody in vivo in SIV- infected infant RMs at the time of ART initiation to define the role of the IL-10 signaling pathway on reservoir establishment. In Aim 3, we will perform IL-10 blockade in vivo in SIV-infected infant RMs on long-term ART to determine the impact of IL-10 signaling on reservoir maintenance. Bulk and single-cell multiomic approaches will be applied in all Aims to identify and validate major immune pathways associated with HIV/SIV reservoirs and/or viral rebound and to advance our understanding of host-pathogen interactions that dictate virus persistence in early life. 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 infant RM models and cutting-edge systems immunology approaches to deeply interrogate pediatric HIV/SIV. With multidisciplinary approaches, synergies across Projects and Cores, and our highly collaborative group of established and early-stage investigators, we are confident that Project 1 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 1 该计划项目申请的总体目标是全面了解复杂的宿主-病原体相互作用对于艾滋病毒储存库播种和持久性至关重要，因此新的治疗方法可以制定真正针对艾滋病毒感染儿童 (CLWH) 独特免疫环境的策略。我们在项目 1 中解决的知识差距是如何建立和维护艾滋病毒储存库受新生儿和儿童免疫系统调节，特别关注 IL-10 和 TGF-β 对免疫系统的作用先天性和适应性免疫功能、胸腺输出、受感染细胞的存活和病毒反弹。生命早期免疫环境的特征与成人不同，包括活跃的胸腺和耐受/调节偏倚，具有显着的 T 辅助细胞 2 和调节性 CD4+ T 细胞。细胞因子 IL-10 和 TGF-β 在婴儿中增加，并且已知 IL-10 可以抑制抗原呈递、T 细胞效应功能和细胞增殖，同时促进中央记忆 CD4+ T 细胞的存活。研究表明，来自感染 SHIV 的幼年恒河猴 (RM) 子集的淋巴结 CD4+ T 细胞分析治疗中断 (ATI) 后病毒血症得到控制，其抗 IL-10 基因特征值得注意。项目 1 中要测试的假设是 IL-10 和 TGF-β 影响 HIV 的程度婴儿储存库和 ATI 后病毒反弹，同时靶向调节 IL-10/TGF-β 信号通路将损害储存库的持久性并增强导致 ATI 后病毒控制的免疫反应。我们将评估婴儿的细胞因子环境如何影响完整的储存库大小、病毒反弹和抗病毒药物在目标 2 中，我们将在 SIV-体内使用抗 IL-10 单克隆抗体进行 IL-10 阻断。在开始 ART 时受感染的婴儿 RM 以确定 IL-10 信号通路对储存库的作用在目标 3 中，我们将在接受长期 ART 的 SIV 感染婴儿 RM 中进行体内 IL-10 阻断。确定 IL-10 信号传导对储存库维护的影响。将应用于所有目标，以识别和验证与 HIV/SIV 储存库相关的主要免疫途径和/或病毒反弹，并增进我们对决定病毒的宿主-病原体相互作用的理解更好地了解艾滋病毒携带者对先天性和适应性的脆弱性。免疫压力将推动治疗 CLWH 的明智方法。这项研究建立在我们的基础上。婴儿 RM 模型和尖端系统免疫学方法的专业知识可深入探究通过多学科方法、跨项目和核心的协同作用以及我们的高度由已建立的和早期研究人员组成的合作小组，我们相信项目 1 将导致关于儿科艾滋病毒储存库的免疫调节和免疫功能障碍的重要发现。我们的使命是将这些发现转化为临床试验方案，以推进儿童治愈研究患有艾滋病毒。