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

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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.