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的调节，特别关注IL-10和转化生长因子-β在 先天性和获得性免疫功能、胸腺输出、受感染细胞的存活和病毒反弹。多重 早期生命免疫环境的特点与成人不同，包括活跃的胸腺和 耐受性/调节性偏向，突出的T辅助细胞2和调节性CD4+T细胞。消炎药 细胞因子IL-10和转化生长因子-β在婴儿中增加，已知IL-10抑制抗原提呈，T细胞 效应器功能，促进细胞增殖，同时促进中枢记忆的CD4+T细胞存活。我们有 显示来自希沃克病毒感染的婴儿恒河猴(RMS)的淋巴组织CD4+T细胞亚群 分析治疗中断(ATI)后的受控病毒血症以抗IL-10基因特征而显著。 在项目1中要检验的假设是IL-10和转化生长因子-β影响艾滋病毒的大小 靶向调控IL-10/转化生长因子-β信号通路与婴幼儿急性心肌梗死后病毒反弹 将损害储蓄者的持久性，并增强免疫反应，从而导致ATI后病毒控制。在目标1中， 我们将评估婴儿体内的细胞因子环境如何影响完整的储存库大小、病毒反弹和抗病毒作用。 豁免权。在目标2中，我们将在SIV中使用抗IL-10的单抗在体内进行IL-10的阻断。 在ART开始时感染婴儿RMS以确定IL-10信号通路在库上的作用 建制派。在目标3中，我们将对SIV感染的婴儿RMS进行体内IL-10阻断，进行长期的ART 确定IL-10信号对储集层维护的影响。散装和单细胞多组学方法 将应用于所有目标，以识别和验证与艾滋病毒/SIV宿主相关的主要免疫途径 和/或病毒反弹，并促进我们对决定病毒的宿主-病原体相互作用的理解 早期生活中的坚持不懈。更好地了解艾滋病毒宿主对先天和适应性的脆弱性 免疫压力将推动治疗慢性肝病的知情方法。提出的研究是建立在我们的 具有婴儿RM模型和尖端系统免疫学方法的专业知识，可深入询问 儿童艾滋病毒/SIV。借助多学科方法、跨项目和核心的协同效应，以及我们高度 由成熟和早期调查人员组成的合作小组，我们相信项目1将导致 有关儿童艾滋病毒蓄积物的免疫调节和免疫功能障碍的重要发现。它是 我们的使命是将这些发现转化为临床试验方案，以推进治疗儿童的研究 艾滋病毒携带者。

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.