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

项目摘要 患有围产期获得性艾滋病毒感染（PHIV）的儿童以及暴露于艾滋病毒但未感染的儿童 (HEU)他们将面临一生的健康和福祉挑战，包括增长赤字， 神经发育我们对艾滋病毒感染和/或艾滋病毒暴露如何影响人类健康的理解仍然存在差距。 直接影响出生时和一生的健康。填补这些空白对于确定更好的干预措施至关重要， 这些受艾滋病毒影响的人群。可以对血液样本进行非侵入性的表观遗传分析 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感染的机制， 影响长期健康。我们的长期目标是确定易于测量的血液生物标志物， 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 随着它们在生命过程中的生长和衰老而变化。这项补助金的目的是描述独立的 HIV感染和HIV暴露对婴儿表观遗传特征的影响，以及这些特征的贡献 增长成果。对当代人群的研究通常无法理清艾滋病毒的影响 从抗逆转录病毒治疗（ART）对DNA甲基化谱的影响来看， ART今天，但了解这些独立的影响是至关重要的，以确定机制的长期 健康后果和潜在干预点。这一创新和具有成本效益的项目将利用 NICHD数据和标本中心（DASH）提供大量历史数据和血液生物标本 来自母亲和婴儿队列研究（MICS），一项针对孕妇的前瞻性流行病学队列研究 1985-1991年间在纽约市进行的携带和不携带HIV的患者（n=450）及其后代的研究。重要的是， 该队列中没有使用ART。我们的中心假设是，婴儿的DNA甲基化谱直接与 受HIV感染和/或在没有ART的情况下HIV暴露的改变，并且这些甲基化谱 导致PHIV和HEU儿童报告的生长受损。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 综合Illumina MethylationEPIC BeadChip阵列用于表征储存血液中的DNA甲基化 从多指标类集调查中获得的生物标本，以实现以下具体目标：1）检查艾滋病毒与 3个月和12个月时婴儿的感染/暴露和DNA甲基化; 2）评估婴儿 DNA甲基化与受艾滋病毒影响的儿童4年的生长结果相关。研究 在这个探索性的R21中提出的是重要的，因为它将识别HIV感染的DNA甲基化特征 和艾滋病毒暴露的婴儿，并奠定了基础，以进一步调查长期的健康后果， HIV诱导的DNA甲基化变化在受HIV影响的不断增长的人群中此外，调查结果显示， 这项研究可能有助于了解影响早期生命生长和发育的其他条件。

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.