The role of Trained Immunity and Mitochondrial dysfunction on INnate immunity in children and adolescents aGing with PHIV (TIMING-PHIV)

项目概要： 人类免疫缺陷病毒（HIV）与持续的免疫激活和功能障碍有关， 在感染后早期启动的抑制性抗逆转录病毒治疗（ART）期间。围产期获得性艾滋病毒 （PHIV）感染和终身ART可能会改变免疫系统的发育和功能。的 艾滋病毒和ART在子宫内的暴露，几十年的ART治疗，较老的毒性ART的持久影响， 线粒体毒性和长期次优的依从性已知随着长期ART使用而发生， 令人更加关切是，儿童和青少年中艾滋病毒和抗逆转录病毒疗法的后遗症可能更为常见， 可能比成年人更具破坏性。更好地了解PHIV的免疫功能障碍至关重要，因为它 通常更容易在早期阶段限制甚至逆转合并症。我们正在研究 在乌干达的一组青少年中， 艾滋病毒感染儿童和艾滋病毒阳性儿童的免疫状况差异。这些差异可能是由训练有素的 免疫是先天免疫系统的细胞（例如单核细胞、巨噬细胞和自然免疫细胞）通过免疫系统的细胞（例如单核细胞、巨噬细胞和自然免疫细胞）产生免疫应答的过程。 杀伤细胞）被重新编程以不同地响应随后暴露于微生物产物， 促炎脂质最近的研究，包括我们自己的研究，表明ART暴露也可能有助于 免疫细胞活化的改变，可能通过降低线粒体功能， 调节细胞内信号级联。从这一建议中获得的知识可能是大量的， 并从翻译的角度将奠定基础，以确定关键途径与生物，临床， 对进入成年期的青少年的预后相关性。这些结果可以提供信息 干预试验，以减轻与免疫激活相关的合并症的发展。我们建议： 目的1：测量先天免疫谱（即单核细胞和NK细胞）在青少年与非艾滋病毒， 乌干达和美国。 目的2：确定训练的免疫力在先天免疫调节中的作用， 乌干达艾滋病病毒感染。 目的3：评估线粒体功能如何在先天免疫谱中纵向发挥作用， 乌干达感染和未感染艾滋病毒的青少年。 该建议结合了一个特征良好的队列儿童与非PHIV与离体和体外 免疫细胞表型和功能的评估。我们将使用高维流式细胞术分析， 单细胞转录谱分析，以及深入的分析方法，以确定潜在的机制 慢性暴露于ART、微生物制品以及临床和环境因素可能导致 先天免疫细胞激活或功能障碍。这是一个非常成功的合作， 研究小组成员和我们都有能力执行这项创新项目。

Project Summary: Human immunodeficiency virus (HIV) is associated with persistent immune activation and dysfunction, even during suppressive antiretroviral therapy (ART) that was initiated early post-infection. Perinatally acquired HIV (PHIV) infection and lifelong ART likely alter the development and function of the immune system. The exposure of HIV and ART in utero, the decades of ART therapy, the lasting effects of older toxic ART with mitochondrial toxicity and the long-term sub-optimal adherence known to occur with prolonged ART use, heighten concern that sequelae of HIV and ART in children and adolescents may be more frequent and potentially more devastating than in adults. Better understanding of immune dysfunction in PHIV is crucial, as it is often easier to limit or even reverse comorbidities at an early stage. We are exploring the consequences of PHIV and its treatment with ART in a cohort of adolescents in Uganda and have reported significant differences in the immune profiles of HIV- and HIV+ children. These differences may be driven by trained immunity, a process by which cells of the innate immune system (e.g. monocytes, macrophages and natural killer cells) are reprogrammed to respond differently to subsequent exposure to microbial products and proinflammatory lipids. Recent studies, including our own, demonstrate that ART exposure may also contribute to alterations in immune cell activation, potentially through decreased mitochondrial function and through modulation of intracellular signaling cascades. The knowledge gained from this proposal could be substantial, and from a translational perspective will lay the foundation to identify key pathways with biological, clinical, and prognostic relevance for adolescents who are advancing into adulthood. These results could inform intervention trials to mitigate the development of comorbidities associated with immune activation. We propose: Aim 1: To measure innate immune profiles (i.e monocytes and NK cells) in adolescents with and without HIV in Uganda and the United States. Aim 2: To identify the role of trained immunity in innate immune modulation in adolescents with and without HIV infection in Uganda. Aim 3: To evaluate how mitochondrial function plays a role in innate immune profiles longitudinally in adolescents with and without HIV in Uganda. This proposal combines a well-characterized cohort of children with and without PHIV with ex vivo and in vitro assessments of immune cell phenotype and function. We will use high-dimensional flow cytometry analyses, single cell transcriptional profiling, and an in-depth analytical approach to define the potential mechanisms whereby chronic exposure to ART, microbial products, and clinical and environmental factors may contribute to innate immune cell activation or dysfunction. This is a continuation of a highly successful collaboration among the study team members and we are well positioned to perform this innovative project.