Leveraging NICHD DASH biospecimens to isolate the effects of HIV infection and HIV exposure on epigenetic profiles in infants

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PROJECT SUMMARY Children living with perinatally-acquired HIV infection (PHIV) as well as those exposed to HIV, but uninfected (HEU) face a lifetime of challenges to their health and well-being, including deficits in growth and neurodevelopment. There continue to be gaps in our understanding of how HIV infection and/or HIV exposure directly impact health at birth and throughout life. Filling these gaps is essential to define better interventions in these populations affected by HIV. Epigenetic analyses that can be non-invasively conducted on blood samples may offer tremendous opportunities to understand the mechanisms by which early HIV infection and HIV exposure affect long-term health. Our long-term goal is to identify easy-to-measure blood-based biomarkers that reflect HIV infection and/or HIV exposure and predict subsequent risk for morbidity in children affected by HIV as they grow and age throughout the life course. The objective of this grant is to characterize the independent effects of HIV infection and HIV exposure on epigenetic profiles in infants, and the contribution of these profiles to growth outcomes. Studies in contemporary populations are typically unable to disentangle the effects of HIV from the effects of antiretroviral therapy (ART) on DNA methylation profiles given the nearly complete use of ART today, yet understanding these independent effects is critical for defining mechanisms underlying long-term health consequences and potential points of intervention. This innovative and cost-effective project will leverage a wealth of historical data and blood biospecimens available in the NICHD Data and Specimen Hub (DASH) from the Mothers and Infants Cohort Study (MICS), a prospective, epidemiologic cohort study of pregnant women with and without HIV (n=450) and their offspring conducted in New York City between 1985-1991. Importantly, there was no ART use in the cohort. Our central hypothesis is that DNA methylation profiles in infants are directly subject to alteration by HIV infection and/or HIV exposure in the context of no ART, and these methylation profiles contribute to compromised growth reported in PHIV and HEU children. Our interdisciplinary research team is comprised of experts in pediatric HIV, epigenetics, infant growth and development, epidemiology, and biostatistics. We will employ state-of-the-art experimental and analytical approaches and utilize the comprehensive Illumina MethylationEPIC BeadChip array to characterize DNA methylation in stored blood biospecimens from MICS towards the following specific aims: 1) To examine the association between HIV infection/exposure and DNA methylation in infants at 3 and 12 months; 2) To evaluate the extent to which infant DNA methylation is associated with growth outcomes through 4 years in HIV-affected children. The research proposed in this exploratory R21 is significant because it will identify DNA methylation signatures of HIV infection and HIV exposure in infants and lay a foundation to further investigate the long-term health consequences of HIV-induced DNA methylation changes in a growing population affected by HIV. In addition, findings from this study may provide insight into other conditions affecting early life growth and development.