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：
10393702
负责人：
JESSE J KWIEK
金额：
$ 73.08万
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/10393702
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 Persons 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.

抽象的尽管艾滋病毒的孕妇终身三重抗逆转录病毒疗法（ART）迅速扩大（WLH），WLH所生的孩子继续存在低出生体重（LBW），发病率和与不患艾滋病毒的妇女出生的婴儿相比，死亡率。虽然 LBW和儿童生存减少的研究已经很好地研究，与艾滋病毒或艺术联系的生物学机制以及 LBW没有很好地描述。为了更好地了解艾滋病毒/艺术如何增加LBW的风险，我们利用正在进行的，良好的艾滋病毒妇女的妇女队列参加了数据驱动的持续质量的试验干预刚果民主共和国金沙萨的长期艺术成果；我们的具体重点是在与HIV相关的炎症，免疫激活和微生物群落上通用艺术。一组600名艾滋病毒妇女的艺术和600名HIV阴性控制将招募艾滋病毒暴露的未感染（HEU）和艾滋病毒暴露（HU）婴儿产后交付和最多12个月，以确定艾滋病毒/艺术诱导的胎盘功能障碍（AIM 1）或微生物营养不良（AIM 2）调节LBW的风险和随后的婴儿死亡率。使用生物学从这些妇女那里获得的标本，我们将记录组织病理学异常（例如坏死）和炎症，免疫激活和微生物易位标记的水平。我们还将使用机器学习和生态系统建模的尖端微生物组和病毒瘤工具包评估这些实体与炎症与LBW之间的关联的方法，以及在硅测试中从功能分析得出的无数机械假设。我们希望这些完成互补目标将提供有关与增加风险相关的生物学机制的见解在艾滋病毒暴露的婴儿中LBW。这种见解最终可以确定最佳的HIV治疗或护理怀孕WLH的方式：一种促进孕产妇健康的一种，可以防止艾滋病毒母亲到孩子传播，并最大化婴儿生存。