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

项目总结： 人类免疫缺陷病毒(HIV)与持续性免疫激活和功能障碍有关，甚至 在感染后早期开始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 艾滋病病毒(PHIV)感染和终身抗逆转录病毒可能会改变免疫系统的发育和功能。这个 在子宫内暴露艾滋病毒和ART，几十年的ART治疗，旧的有毒ART的持久影响 线粒体毒性和已知的长期使用抗逆转录病毒药物后出现的长期次优粘连， 儿童和青少年中艾滋病毒和抗逆转录病毒治疗后遗症可能更加频繁和 可能比成年人更具破坏性。更好地了解艾滋病毒的免疫功能障碍是至关重要的，因为它 在早期阶段往往更容易限制甚至逆转共病。我们正在探索这样做的后果 在乌干达的一群青少年中进行艾滋病病毒及其抗逆转录病毒治疗，并报告了显著的 艾滋病毒携带者和艾滋病毒儿童免疫特征的差异。这些差异可能是由训练有素的人推动的 免疫：先天免疫系统的细胞(如单核细胞、巨噬细胞和天然免疫细胞) 杀伤细胞)被重新编程，以对随后暴露于微生物产品和 促炎症脂质。最近的研究，包括我们自己的研究表明，接触艺术也可能起到作用 免疫细胞激活的改变，可能是通过线粒体功能降低和通过 细胞内信号级联的调制。从这项提议中获得的知识可能是大量的， 从翻译的角度将奠定基础，以确定关键途径与生物学、临床和 对即将步入成年期的青少年的预后相关性。这些结果可能会告诉我们 干预试验，以减轻与免疫激活相关的共病的发展。我们建议： 目的1：检测感染和不感染HIV的青少年的天然免疫功能(即单核细胞和NK细胞)。 乌干达和美国。 目的2：确定训练性免疫在先天性免疫调节中的作用 乌干达的艾滋病毒感染。 目的3：评价线粒体功能在先天性免疫功能中的作用。 乌干达感染和不感染艾滋病毒的青少年。 这项建议结合了一组具有良好特征的艾滋病毒携带者和非艾滋病毒携带者与体外和体外儿童。 免疫细胞表型和功能的评估。我们将使用高维流式细胞仪分析， 单细胞转录图谱，以及确定潜在机制的深入分析方法 因此，长期接触抗逆转录病毒药物、微生物产品以及临床和环境因素可能会导致 先天免疫细胞激活或功能障碍。这是以下公司非常成功的合作的延续 研究团队成员和我们都处于有利地位，可以执行这个创新的项目。

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.