HIV/ART, low birth weight, and mortality in HIV-exposed uninfected children: a translational mechanistic study

HIV/ART、低出生体重和暴露于 HIV 的未感染儿童的死亡率：一项转化机制研究

基本信息

批准号：
10258233
负责人：
JESSE J KWIEK
金额：
$ 77.24万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-15 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10258233
关键词：
Address Age-Months Antibodies Atopobium vaginae Attention Biological Birth Blood Blood Circulation Cardiovascular Diseases Caring Child Clinical Clinical Data Data Democratic Republic of the Congo Development Diarrhea Ecosystem Enrollment Exposure to Feces Female of child bearing age Fetal Development Fetal Growth Retardation Fetus Functional disorder Genetic Diseases Growth HIV HIV Seronegativity HIV antiretroviral HIV therapy HIV-exposed uninfected infant Health Human Microbiome Hypertension Infant Infant Health Infant Mortality Inflammation Infrastructure Intervention Intervention Studies Laboratories Link Low Birth Weight Infant Low Prevalence Machine Learning Maternal Health Measures Mediation Metagenomics Modality Modeling Morbidity - disease rate Mother-to-child HIV transmission Necrosis Non-Insulin-Dependent Diabetes Mellitus Nutrient Organism Outcome Oxygen Pathway interactions Placenta Plasma Postpartum Period Pregnancy Pregnancy Outcome Pregnant Women Premature Birth Production Risk Source Specimen Spottings Swab Testing Third Pregnancy Trimester Time Tissues Umbilical Cord Blood Vaginal delivery procedure Vascular Diseases Woman adverse birth outcomes antiretroviral therapy cohort dysbiosis fetal follow-up immune activation improved in silico in utero infant gut microbiome infant infection inflammatory marker insight metatranscriptomics microbial microbial community microbiome mortality mortality risk neonate prenatal exposure prenatal therapy prevent recruit scale up therapy development transmission process vaginal infection vaginal microbiome vaginal microbiota virome

项目摘要

Abstract Despite the rapid scale-up of lifelong triple antiretroviral therapy (ART) among pregnant women living with HIV (WLH), children born to WLH continue to have an increased risk of low birth weight (LBW), morbidity, and mortality compared to infants born to women who are not living with HIV. Although the association between LBW and decreased child survival has been well studied, the biological mechanisms linking HIV or ART and LBW are not well described. To better understand how HIV/ART increases the risk of LBW, we leverage an ongoing, well-characterized cohort of women living with HIV enrolled in a trial of data-driven continuous quality intervention to improve long term outcomes of ART in Kinshasa, Democratic Republic of Congo; our specific focus is on HIV-associated inflammation, immune activation, and microbial communities in the context of universal ART. A cohort of 600 women living with HIV on ART and 600 HIV-negative control along with their HIV-exposed un-infected (HEU) and HIV unexposed (HU) infants will be recruited and followed up through delivery and up to 12 months postpartum to determine how HIV/ART-induced placental dysfunction (Aim 1) or microbial dysbiosis (Aim 2) modulate the risk of LBW and subsequent infant mortality. Using biological specimen obtained from those women, we will document histopathologic placental abnormalities (e.g. necrosis) and measure levels of markers of inflammation, immune activation, and microbial translocation. We will also use a cutting-edge microbiome and virome toolkit with machine learning and ecosystem modeling approaches to evaluate associations between these entities and inflammation and LBW, as well as in silico test myriad mechanistic hypotheses derived from functional analyses. We expect that completion of these complementary aims will provide insight into the biological mechanism(s) associated with increased risk of LBW among HIV-exposed infants. This insight could ultimately identify an optimal HIV- treatment or care modality for pregnant WLH: one which promotes maternal health, prevents HIV mother-to-child transmission, and maximizes infant survival.

抽象的尽管在感染艾滋病毒的孕妇中迅速扩大了终身三联抗逆转录病毒疗法（ART） (WLH)，WLH 出生的儿童的低出生体重 (LBW)、发病率和发病率的风险继续增加与未感染艾滋病毒的妇女所生婴儿的死亡率相比。虽然之间的关联低体重和儿童存活率下降已得到充分研究，艾滋病毒或抗逆转录病毒疗法与 LBW 没有得到很好的描述。为了更好地了解 HIV/ART 如何增加 LBW 的风险，我们利用持续的、特征明确的艾滋病毒感染女性群体参加了一项数据驱动的持续质量试验在刚果民主共和国金沙萨进行干预，以改善抗逆转录病毒治疗的长期效果；我们具体的重点是 HIV 相关炎症、免疫激活和微生物群落通用艺术。一组 600 名接受 ART 治疗的艾滋病毒感染者和 600 名艾滋病毒阴性控制者以及她们的将招募 HIV 暴露未感染 (HEU) 和 HIV 未暴露 (HU) 婴儿并通过以下方式进行随访：分娩和产后 12 个月内确定 HIV/ART 如何诱发胎盘功能障碍（目标 1）或微生物失调（目标 2）调节低出生体重和随后的婴儿死亡率的风险。使用生物从这些女性身上获取样本，我们将记录组织病理学胎盘异常（例如坏死）并测量炎症、免疫激活和微生物易位标记物的水平。我们还将使用具有机器学习和生态系统建模功能的尖端微生物组和病毒组工具包评估这些实体与炎症和低出生体重之间关联的方法以及计算机测试来自功能分析的无数机械假设。我们预计这些工作的完成互补的目标将深入了解与增加的风险相关的生物机制艾滋病毒暴露婴儿中的低出生体重。这种见解最终可以确定最佳的艾滋病毒治疗或护理怀孕 WLH 的方式：一种促进孕产妇健康、预防艾滋病毒母婴传播的方式，并最大限度地提高婴儿的生存率。