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: 10701471
• 负责人: Maud Mavigner
• 金额: $ 55.57万
• 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/10701471
• 关键词: Adaptive Immune System; Address; Adolescence; Adult; Age; Antibodies; Antigens; Biological Assay; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Child; Childhood; Complex; Data; Development; Environment; Excision; Functional disorder; Genetic Transcription; HIV; HIV Infections; Immune; Immune System Diseases; Immune system; Immunity; Immunologics; Immunology; Immunophenotyping; In Vitro; Infant; Infection; Innate Immune System; Interruption; Investigation; Knowledge; Life; Macaca mulatta; Maintenance; Mediating; Mission; Modeling; Morbidity - disease rate; Nature; Neonatal; Output; Production; Reproducibility; Research; Research Personnel; Role; SIV; T-Lymphocyte; Testing; Thymus Gland; Viral; Viral Physiology; Viral reservoir; Viremia; Virus; antiretroviral therapy; clinical trial protocol; comparative; efficacy evaluation; humanized mouse; immunoregulation; in vitro Model; in vivo; integration site; interdisciplinary approach; microbial; mortality; multiple omics; novel; pathogen; pediatric human immunodeficiency virus; perinatal HIV; perinatal period; pressure; programs; simian human immunodeficiency virus; synergism; transcriptomics; viral rebound

ABSTRACT – Project 2 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 2 is how the establishment and maintenance of HIV reservoirs are regulated by the neonatal and childhood immune system, with specific focus on the cytolytic and non-cytolytic antiviral role of CD8+ T cells. The drivers of reservoir persistence in CLWH are incompletely understood and the complexity of the pediatric innate and adaptive immune system across developmental stages contributes to the challenge of a finding cure for HIV. Mounting evidence in adult models implicates CD8+ T cells as being required for maintaining HIV suppression under antiretroviral therapy (ART) and we have recently found that the viral reservoir seeded after infection does not depend on the classical cytolytic function of antigen-specific CD8+ T cells. The hypothesis to be tested in Project 2 is that the CD8+ T cell-mediated HIV/SIV pro-latency effect will be reproducible in pediatric models; however, distinct features of this non-classical role for CD8+ T cells may be influenced by the regulatory immune environment in early life. In Aim 1, we will develop pediatric in vitro models to thoroughly investigate the mechanisms involved in CD8+ T cell-mediated control of HIV/SIV latency in infants and children via comparative immunophenotyping, transcriptomic, and virological analyses in presence or absence of CD8+ T cells. In Aim 2, we will conduct a proof-of-principle in vivo study using experimental antibody mediated CD8+ cell depletion in rhesus macaque (RM) infants prior to infection with SIVmac239M. To assess the role of CD8+ T cells in SIV reservoir establishment we will compare viral dynamics and viral reservoir size/diversity/integration sites on ART and virus rebound after ART interruption between CD8-depleted and undepleted RM infants. In Aim 3, antibody-mediated CD8+ cell depletion will be performed in SIVmac239M-infected RM infants after long-term ART with and without an LRA to test the extent to which removal of CD8+ T cells disrupts reservoir maintenance. CD8+ T cell-mediated mechanisms involved in latency reversal will be further assessed through multiomic analyses. 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, state-of-the-art reservoir assays, and T cell immunology 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 2 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 2 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儿童（CLWH）独特免疫环境的策略。 我们在项目 2 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，特别关注细胞溶解性和非细胞溶解性 CD8+ T 细胞的抗病毒作用。 CLWH 中储层持续存在的驱动因素尚不完全了解， 儿科先天性和适应性免疫系统在各个发育阶段的复杂性有助于 寻找艾滋病毒治疗方法的挑战。成人模型中越来越多的证据表明 CD8+ T 细胞 在抗逆转录病毒治疗（ART）下维持艾滋病毒抑制所需，我们最近发现 感染后接种的病毒库不依赖于抗原特异性的经典溶细胞功能 CD8+ T 细胞。项目 2 中要测试的假设是 CD8+ T 细胞介导的 HIV/SIV 促潜伏期 效果将在儿科模型中重现；然而，CD8+ T 这种非经典角色的独特特征 细胞在生命早期可能会受到调节性免疫环境的影响。在目标 1 中，我们将开发儿科 体外模型彻底研究 CD8+ T 细胞介导的 HIV/SIV 控制机制 通过比较免疫表型、转录组学和病毒学分析，确定婴儿和儿童的潜伏期 CD8+ T 细胞的存在或不存在。在目标 2 中，我们将使用以下方法进行体内原理验证研究： 恒河猴 (RM) 婴儿在感染前实验抗体介导的 CD8+ 细胞耗竭 SIVmac239M。为了评估 CD8+ T 细胞在 SIV 储存库建立中的作用，我们将比较病毒动力学 ART 上的病毒库大小/多样性/整合位点以及 ART 中断后的病毒反弹 CD8 耗尽和未耗尽的 RM 婴儿。在目标 3 中，将进行抗体介导的 CD8+ 细胞耗竭 在接受或不接受 LRA 的长期 ART 后感染 SIVmac239M 的 RM 婴儿中进行测试，以测试感染的程度 CD8+ T 细胞的去除会破坏储存库的维护。 CD8+ T 细胞介导的潜伏机制 将通过多组学分析进一步评估逆转。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。这 拟议的研究建立在我们在婴儿 RM 模型、最先进的储库检测和 T 细胞方面的专业知识的基础上 免疫学深入研究儿科 HIV/SIV。通过多学科方法、跨领域协同作用 项目和核心，以及我们由已建立的和早期研究人员组成的高度协作的团队，我们 相信项目 2 将带来关于儿科 HIV 免疫调节的重要发现 储库和免疫功能障碍。我们的使命是将这些发现转化为临床试验方案 推进治疗艾滋病毒儿童的研究。