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

项目摘要 该提案将使用NIH存档的纵向心脏成像数据和血液生物标本 儿科艾滋病毒/艾滋病队列研究（PHACS），通过研究艾滋病毒/艾滋病的相互作用， 疾病关键免疫细胞单核细胞的表观遗传功能障碍与纵向心脏结构之间的关系 在围产期感染艾滋病毒的青少年和感染艾滋病毒的年轻人以及艾滋病毒暴露者中， 未受感染的人（HEU）。越来越多的证据表明，围产期感染艾滋病毒并 在整个发育过程中暴露于抗逆转录病毒治疗（ART）的儿童， 异常和心脏代谢疾病的风险增加。全身性免疫炎症和 线粒体功能障碍与艾滋病毒/抗逆转录病毒疗法暴露和生活在 感染了艾滋病毒然而，人们对围产期艾滋病毒感染的生物学机制仍然了解有限。 感染和纵向暴露于ART相互作用以改变免疫细胞功能，导致进行性 有害的心脏变化这项研究的新前提是，早期接触艾滋病毒和 儿童时期的纵向ART在促炎性细胞因子的表观基因组上留下了持久的生物记忆。 免疫细胞，以全身炎症和线粒体功能障碍水平增加为特征 与左心室应激和心肌细胞损伤的进行性有害变化有关。使用 系统生物学方法，我们将研究从活的单核细胞中获得的富集的单核细胞的表观遗传特征， 在120例HIV阳性青少年和年轻成人中， 来自NIH支持的PHACS子研究的11.3岁和80名HEU青年的平均ART暴露。Epigenetics 数据将与现有的纵向超声心动图数据和炎症的生物标志物数据整合， 心脏损伤和线粒体功能目的1将鉴定纯化单核细胞的表观遗传特征 与120名HIV阳性青少年和年轻人以及80名年龄/性别的心脏功能和生物标志物相关 儿科HIV/AIDS队列研究（PHACS）的匹配HEU参与者。目标2将评估是否 三年内纵向超声心动图测量的变化与单核细胞DNA的差异有关 甲基化模式该研究方法将定义120个免疫细胞类型特异性表观基因组， 艾滋病毒阳性青少年和青年以及80名年龄/性别匹配的高浓缩铀青少年和青年， 确定在整个发育过程中纵向暴露于HIV/ART如何重塑免疫细胞 表观基因导致进行性心功能障碍。了解艾滋病毒/ART对亚临床 通过表观遗传学的透镜， 这对于确定亚临床心脏异常的新生物标志物和告知公共卫生政策至关重要 以及未来干预试验的设计，旨在优化整个生命周期的心血管健康， 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.