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

利用 NICHD DASH 生物样本来分离 HIV 感染和 HIV 暴露对婴儿表观遗传特征的影响

• 批准号: 10161102
• 负责人: Stephanie Shiau
• 金额: $ 24.16万
• 依托单位: RBHS-SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-21 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10161102
• 关键词: Adaptive Immune System; Affect; Age; B-Lymphocytes; Behavior; Biometry; Birth; Blood; Blood specimen; Cell Maturation; Child; Cohort Studies; Consequences of HIV; Cytosine; DNA; DNA Methylation; Data; Environment; Epidemiology; Epigenetic Process; Exposure to; Face; Foundations; Genes; Genomics; Goals; Grant; Growth; Growth and Development function; Guanine; HIV; HIV Infections; HIV therapy; Health; Infant; Interdisciplinary Study; Intervention; Life; Life Cycle Stages; Link; Longitudinal Studies; Measures; Metabolic Diseases; Methylation; Morbidity - disease rate; Mother-to-child HIV transmission; Mothers; National Institute of Child Health and Human Development; Neurodevelopmental Deficit; New York City; Obesity; Outcome; Pattern; Perinatal; Perinatal Epidemiology; Personal Satisfaction; Population; Pregnancy; Pregnant Women; Regulation; Reporting; Research; Risk; Site; Specimen; Time; Work; aged; antiretroviral therapy; bead chip; blood-based biomarker; cohort; cost effective; epigenetic marker; epigenome; improved; in utero; innovation; inorganic phosphate; insight; neurodevelopment; offspring; pediatric human immunodeficiency virus; prevent; programs; prospective

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.

项目概要 感染围产期艾滋病毒 (PHIV) 的儿童以及接触艾滋病毒但未感染的儿童 （HEU）的健康和福祉终其一生都面临着挑战，包括增长不足和 神经发育。我们对艾滋病毒感染和/或艾滋病毒暴露如何发生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。可对血液样本进行非侵入性的表观遗传学分析 可能会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 接触会影响长期健康。我们的长期目标是确定易于测量的血液生物标志物 反映 HIV 感染和/或 HIV 暴露并预测受 HIV 影响的儿童随后的发病风险 随着他们在生命历程中的成长和衰老。这笔赠款的目的是描绘独立的特征 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阐明艾滋病毒的影响 鉴于几乎完全使用抗逆转录病毒疗法 (ART) 对 DNA 甲基化谱的影响 今天的 ART，但了解这些独立的影响对于定义长期潜在机制至关重要 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 数据和样本中心 (DASH) 提供大量历史数据和血液生物样本 来自母亲和婴儿队列研究 (MICS)，这是一项针对孕妇的前瞻性流行病学队列研究 1985 年至 1991 年间，在纽约市对感染和未感染艾滋病毒 (n=450) 及其后代进行了研究。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 在没有 ART 的情况下，可能会因 HIV 感染和/或 HIV 暴露而发生改变，并且这些甲基化谱 导致 PHIV 和 HEU 儿童生长发育受损。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 全面的 Illumina MmethylationEPIC BeadChip 阵列可表征储存血液中的 DNA 甲基化 MICS 生物样本的目的如下： 1) 检查 HIV 之间的关联 3 个月和 12 个月婴儿的感染/暴露和 DNA 甲基化； 2) 评估婴儿的程度 DNA 甲基化与受 HIV 影响的儿童 4 岁时的生长结果相关。研究 该探索性 R21 中提出的方案具有重要意义，因为它将识别 HIV 感染的 DNA 甲基化特征 和婴儿的艾滋病毒暴露情况，并为进一步调查艾滋病毒的长期健康后果奠定基础 在越来越多的受艾滋病毒影响的人群中，艾滋病毒引起的 DNA 甲基化发生变化。此外，本次调查的结果 研究可以深入了解影响早期生命成长和发展的其他条件。