Epigenetic dysregulation of inflammation linked to longitudinal cardiac toxicity in perinatal HIV infection

项目摘要 这项提案将使用NIH的纵向心脏成像存档数据和血液生物标本 儿科HIV/AIDS队列研究(PHACS)通过研究相互作用促进儿科HIV/AIDS研究 致病免疫细胞单核细胞表观遗传功能障碍与心脏纵向结构的关系 在围产期感染的青少年和艾滋病毒携带者和接触艾滋病毒的年轻人中 未感染(HEU)的个人。越来越多的证据表明，在围产期感染艾滋病毒并患有 在整个发育过程中一直接受抗逆转录病毒治疗(ART)的人都记录了亚临床心脏病 心脏代谢性疾病的风险增加。全身性免疫炎症和 线粒体功能障碍与HIV/ART暴露和生活在儿童中的心脏异常有关 艾滋病毒携带者。然而，对围产期艾滋病毒的生物学机制的了解仍然有限。 感染和长期暴露于ART相互作用，改变免疫细胞功能，导致进行性 有害的心脏变化。这项拟议研究的新前提是，早期接触艾滋病毒和 童年时期的纵向艺术在促炎性疾病的表观基因组上留下了持久的生物记忆 免疫细胞，以全身炎症水平增加和线粒体功能障碍为特征 与左心室压力和心肌细胞损害的渐进性有害变化有关。使用 系统生物学的方法，我们将检查从可见的 120例HIV青少年和青壮年患者的外周血单个核细胞的冷冻保存 平均11.3岁的ART暴露和80名来自NIH的HEU青年支持PHACS子项研究。表观遗传学 数据将与现有的纵向超声心动图数据和炎症生物标记物数据相结合， 心脏损伤和线粒体功能。目标1将鉴定纯化单核细胞的表观遗传学特征 120名HIV青少年和青壮年以及80名年龄/性别与心功能和生物标志物相关 与儿科HIV/AIDS队列研究(PHACS)的HEU参与者相匹配。Aim 2将评估是否 三年来纵向超声心动图测量的变化与单核细胞DNA的差异有关 甲基化模式。研究方法将确定120个免疫细胞类型的特定表观基因组 艾滋病毒青少年和青壮年和80个年龄/性别匹配的HEU青少年和青壮年和 确定在发育过程中长期暴露于艾滋病毒/抗逆转录病毒疗法如何重塑免疫细胞 表观基因组导致进行性心功能障碍。了解HIV/ART对亚临床的影响 通过表观遗传学的透镜，青少年和青年艾滋病毒携带者的心脏异常将是 对识别亚临床心脏异常的新生物标志物和为公共卫生政策提供信息至关重要 以及未来干预试验的设计，旨在优化中国人的心血管健康 感染艾滋病毒的儿童。

Project Summary This proposal will use archived longitudinal cardiac imaging data and blood biospecimens from the NIH Pediatric HIV/AIDS Cohort Study (PHACS) to advance pediatric HIV/AIDS research by studying the interplay between epigenetic dysfunction of disease-critical immune cell monocytes and longitudinal cardiac structure and function in both perinatally infected adolescents and young adults living with HIV and HIV-exposed uninfected (HEU) individuals. Increasing evidence shows that children who perinatally acquired HIV and have been exposed to antiretroviral therapy (ART) throughout development have documented subclinical cardiac abnormalities and an increased risk for cardiometabolic diseases. Systemic immune inflammation and mitochondrial dysfunction have been linked to HIV/ART exposure and cardiac abnormalities in children living with HIV. Yet, there remains a limited understanding of the biological mechanisms by which perinatal HIV infection and longitudinal exposure to ART interact to alter immune cell function leading to progressive deleterious cardiac changes. The novel premise of the proposed study is that early exposure to HIV and longitudinal ART during childhood imprints a durable biological memory on the epigenome of proinflammatory immune cells, as characterized by increased levels of systemic inflammation and mitochondrial dysfunction related to progressive deleterious changes in left ventricular stress and cardiomyocyte damage. Using a systems biology approach, we will examine epigenetic profiles of enriched monocyte cells obtained from viably cryopreserved peripheral blood mononuclear cells (PBMCs) in 120 HIV+ adolescents and young adults with a mean ART exposure of 11.3 years and 80 HEU youth from an NIH supported PHACS sub study. Epigenetics data will be integrated with existing longitudinal echocardiographic data and biomarkers data for inflammation, cardiac injury, and mitochondrial function. Aim 1 will identify epigenetic features in purified monocytes associated with cardiac function and biomarkers in 120 HIV+ adolescents and young adults and 80 age/gender matched HEU participants of the Pediatric HIV/AIDS Cohort Study (PHACS). Aim 2 will evaluate whether changes in longitudinal echocardiographic measures over three years relate to differences in monocyte DNA methylation patterns. The study approach will both define the immune cell-type specific epigenomes of 120 HIV+ adolescents and young adults and 80 age/gender matched HEU adolescents and young adults and determine how longitudinal exposure to HIV/ART throughout development reshapes the immune cell epigenome leading to progressive cardiac dysfunction. Understanding the impacts of HIV/ART on subclinical cardiac abnormalities in adolescents and young adults living with HIV through the lens of epigenetics will be critical to identifying novel biomarkers of subclinical cardiac abnormalities and for informing public health policy and the design of future intervention trials aimed at optimizing cardiovascular health across the lifespan in children living with HIV.