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，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。围产期获得艾滋病毒 （PHIV）感染和终身抗逆转录病毒治疗可能会改变免疫系统的发育和功能。的 子宫内艾滋病毒和抗逆转录病毒疗法的暴露、数十年的抗逆转录病毒治疗、旧的有毒抗逆转录病毒疗法的持久影响 线粒体毒性和已知长期使用 ART 时出现的长期次优依从性， 高度关注儿童和青少年中艾滋病毒和抗逆转录病毒治疗的后遗症可能更加频繁， 可能比成人更具破坏性。更好地了解 PHIV 的免疫功能障碍至关重要，因为 通常更容易在早期阶段限制甚至逆转合并症。我们正在探索后果 在乌干达的一组青少年中，PHIV 及其 ART 治疗已报告显着 HIV 感染者和 HIV 儿童的免疫特征存在差异。这些差异可能是由受过训练的人造成的 免疫，先天免疫系统的细胞（例如单核细胞、巨噬细胞和天然免疫细胞） 杀伤细胞）被重新编程，以对随后接触微生物产品做出不同的反应， 促炎脂质。最近的研究（包括我们自己的研究）表明，接受 ART 治疗也可能有助于 免疫细胞激活的改变，可能是通过线粒体功能下降和通过 细胞内信号级联的调节。从该提案中获得的知识可能是大量的， 从转化的角度来看，将为确定生物学、临床和临床方面的关键途径奠定基础 与进入成年期的青少年的预后相关性。这些结果可以告知 旨在减轻与免疫激活相关的合并症发展的干预试验。我们建议： 目标 1：测量感染和未感染 HIV 的青少年的先天免疫特征（即单核细胞和 NK 细胞） 乌干达和美国。 目标 2：确定经过训练的免疫力在患有和不患有这种疾病的青少年的先天免疫调节中的作用 乌干达的艾滋病毒感染情况。 目标 3：纵向评估线粒体功能如何在先天免疫谱中发挥作用 乌干达感染和未感染艾滋病毒的青少年。 该提案将一组特征明确的感染和未感染 PHIV 的儿童与离体和体外试验相结合 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，以及定义潜在机制的深入分析方法 长期接触抗逆转录病毒疗法、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。这是双方高度成功合作的延续 研究团队成员和我们完全有能力执行这个创新项目。

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.