Immune determinants of pediatric HIV/SIV reservoir establishment and maintenance

摘要-项目1 本计划项目申请的总体目标是全面了解 复杂的宿主-病原体相互作用对于HIV储存库播种和持久性至关重要， 可以制定真正针对艾滋病毒感染儿童（CLWH）独特免疫环境的战略。 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库， 由新生儿和儿童免疫系统调节，特别关注IL-10和TGF-β在 先天性和适应性免疫功能、胸腺输出、感染细胞的存活和病毒反弹。多 生命早期免疫环境的特征与成人不同，包括活跃的胸腺和 致耐受性/调节偏倚，具有突出的T辅助细胞2和调节性CD 4 + T细胞。抗炎 细胞因子IL-10和TGF-β在婴儿中增加，并且已知IL-10抑制抗原呈递、T细胞 效应子功能和细胞增殖，同时促进中枢记忆性CD 4 + T细胞的存活。我们有 显示来自SHIV感染的幼年恒河猴（RM）亚群的淋巴结CD 4 + T细胞， 在分析治疗中断（ATI）后控制的病毒血症中，抗IL-10基因特征值得注意。 在项目1中要检验的假设是IL-10和TGF-β影响HIV感染的程度。 婴儿中的病毒库和ATI后的病毒反弹，而靶向调节IL-10/TGF-β信号通路 将削弱水库的持久性和促进免疫反应，导致后ATI病毒控制。在目标1中， 我们将评估婴儿的细胞因子环境如何影响完整的储库大小、病毒反弹和抗病毒治疗。 免疫力在目的2中，我们将在SIV-1中使用抗IL-10单克隆抗体在体内进行IL-10阻断。 在ART开始时感染的婴儿RM，以确定IL-10信号通路对储库的作用 建立。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信号传导对储层维持的影响。批量和单细胞多组学方法 将在所有目标中应用，以识别和验证与HIV/SIV储库相关的主要免疫途径 和/或病毒反弹，并促进我们对宿主-病原体相互作用的理解， 生命早期的坚持。更好地了解艾滋病毒宿主对先天性和适应性 免疫压力将推动知情的方法来治愈CLWH。这项研究建立在我们的 婴儿RM模型和尖端系统免疫学方法的专业知识， 儿科HIV/SIV。通过多学科方法，项目和核心之间的协同作用，以及我们高度的 我们相信，项目1将导致 关于儿科HIV储库和免疫功能障碍的免疫调节的重要发现。是 我们的使命是将这些发现转化为临床试验方案，以推动儿童治疗研究 感染了艾滋病毒

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.