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

项目总结 患有围产期获得性艾滋病毒感染(PHIV)的儿童以及接触艾滋病毒但未感染的儿童 (HEU)面临着对他们的健康和福祉的终身挑战，包括增长和 神经发育。我们对艾滋病毒感染和/或艾滋病毒暴露的理解仍然存在差距 直接影响出生时和一生的健康。填补这些空白是确定更好的干预措施的关键 这些受艾滋病毒影响的人群。可对血液样本进行非侵入性表观遗传学分析 可能提供巨大的机会来了解早期艾滋病毒感染和艾滋病毒 暴露会影响长期健康。我们的长期目标是识别易于测量的基于血液的生物标志物 反映艾滋病毒感染和/或艾滋病毒暴露，并预测受艾滋病毒影响的儿童随后的发病风险 随着他们在整个生命过程中的成长和衰老。这笔赠款的目的是描述独立的 HIV感染和HIV暴露对婴儿表观遗传学特征的影响以及这些特征的贡献 增长成果。在当代人群中进行的研究通常无法解开艾滋病毒的影响 从抗逆转录病毒治疗(ART)对DNA甲基化的影响来看，几乎完全使用了 然而，理解这些独立的影响对于定义长期的 健康后果和潜在的干预点。这一创新且具有成本效益的项目将利用 NICHD数据和标本中心(DASH)提供了丰富的历史数据和血液生物检疫 来自母婴队列研究(MICS)，这是一项针对孕妇的前瞻性流行病学队列研究 1985-1991年在纽约市进行了有无艾滋病毒(n=450)及其后代的研究。重要的是 队列中没有艺术用途。我们的中心假设是婴儿的DNA甲基化特征直接 在非抗逆转录病毒疗法的情况下，易受艾滋病毒感染和/或艾滋病毒暴露的影响，并且这些甲基化特征 导致艾滋病毒携带者和高尿症患者报告的生长发育受损。我们的跨学科研究团队是 由儿科艾滋病毒、表观遗传学、婴儿生长发育、流行病学和 生物统计学。我们将采用最先进的实验和分析方法，并利用 全光甲基化EPIC珠芯片阵列表征储存血液中DNA甲基化 从MICs中提取生物样本，以达到以下特定目的：1)检查艾滋病毒与 3个月和12个月婴儿的感染/暴露和DNA甲基化；2)评估婴儿 在感染艾滋病毒的儿童中，DNA甲基化与4年后的生长结果有关。这项研究 在此探索性研究中提出的R21具有重要意义，因为它将识别HIV感染的DNA甲基化特征 和婴儿接触艾滋病毒的风险，并为进一步调查艾滋病的长期健康后果奠定基础 在受艾滋病毒影响的不断增长的人口中，艾滋病毒引起的DNA甲基化变化。此外，从这一发现来看， 研究可能提供对影响早期生命生长和发育的其他条件的洞察。

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.