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

训练免疫和线粒体功能障碍对感染 PHIV 的儿童和青少年先天免疫的作用 (TIMING-PHIV)

• 批准号: 10435247
• 负责人: Sahera Dirajlal-Fargo
• 金额: $ 75.91万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-21 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10435247
• 关键词: Adherence; Adolescent; Adult; Aging; Area; Biological; Biological Assay; Cell physiology; Cells; Cellular Metabolic Process; Child; Chronic; Clinical; Collaborations; Cytometry; Data; Development; Environmental Risk Factor; Epigenetic Process; Exposure to; Flow Cytometry; Foundations; Functional disorder; Gastrointestinal tract structure; Gene Expression Profile; Gene Expression Profiling; Genetic Transcription; HIV; HIV Infections; HIV antiretroviral; HIV therapy; HIV-infected adolescents; Immune; Immune System Diseases; Immune system; Immunity; Immunization; In Vitro; Individual; Infection; Inflammasome; Inflammation; Innate Immune System; Intervention Trial; Knowledge; Leukocytes; Link; Lipids; Lipopolysaccharides; Lymphocyte; Macrophage Activation; Malaria; Measurement; Measures; Mediator of activation protein; Metabolism; Mitochondria; Modeling; Morbidity - disease rate; Myeloid Cells; Natural Immunity; Natural Killer Cells; Participant; Pathway interactions; Perinatal; Persons; Pharmaceutical Preparations; Phenotype; Play; Population; Positioning Attribute; Process; Prophylactic treatment; Regimen; Reporting; Risk; Role; Signal Transduction; System; T-Cell Activation; Toxic effect; Training; Treatment-related toxicity; Trimethoprim-Sulfamethoxazole; Uganda; United States; Youth; acute infection; antiretroviral therapy; clinical prognostic; co-infection; cohort; comorbidity; cytokine; experimental study; gastrointestinal; geographic difference; gut dysbiosis; high dimensionality; immune activation; immune system function; immunoregulation; innovation; macrophage; member; microbial; mitochondrial dysfunction; monocyte; mortality; novel; pathogen; polyglucosan; prenatal therapy; single-cell RNA sequencing; therapy development; vaccine development

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.

项目摘要： 人免疫缺陷病毒（HIV）与持续的免疫激活和功能障碍有关，甚至 在抑制性抗逆转录病毒疗法（ART）期间，感染了早期感染。围产期获得的艾滋病毒 （pHIV）感染和终身艺术可能会改变免疫系统的发展和功能。这 在子宫内接触艾滋病毒和艺术，数十年的艺术疗法，旧有毒艺术的持久影响 线粒体毒性和长期次数的依从性，已知随着艺术的使用延长而发生 加剧了人们对儿童和青少年的艾滋病毒和艺术后遗症的关注可能更频繁，并且 可能比成年人更具毁灭性。更好地了解PHIV中免疫功能障碍至关重要，因为 在早期阶段，通常更容易限制甚至逆转合并症。我们正在探索后果 pHIV及其在乌干达的一批青少年中对艺术的治疗，并报告了重要的 HIV和HIV+儿童免疫特征的差异。这些差异可能是由训练的 免疫，这是一个先天免疫系统的细胞（例如单核细胞，巨噬细胞和天然） 重编程的杀伤细胞以对随后接触微生物产物的反应不同，并且 促炎性脂质。最近的研究，包括我们自己的研究表明，艺术曝光也可能有助于 为了改变免疫细胞激活，可能通过线粒体功能降低以及通过 细胞内信号传导级联反应的调节。从这一提议中获得的知识可能很重要， 从转化的角度来看，将奠定基础，以确定生物，临床和 对成年后的青少年的预后相关性。这些结果可以告知 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： 目标1：测量有和没有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：确定受过训练的免疫力在具有和没有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。 目标3：评估线粒体功能如何在纵向中的先天免疫特征中起作用 乌干达有和没有艾滋病毒的青少年。 该提议结合了一个有和没有PHIV的儿童的特征良好的队列，并在体外和体外结合 评估免疫细胞表型和功能。我们将使用高维流式细胞仪分析， 单细胞转录分析和一种深入的分析方法来定义潜在机制 因此，长期暴露于艺术，微生物产品以及临床和环境因素可能有助于 先天免疫细胞激活或功能障碍。这是一个非常成功的合作的延续 研究团队成员和我们在执行这个创新的项目方面处于良好状态。