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

• 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
• 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

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.

摘要 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的规模， (WLH)，WLH出生的儿童继续有低出生体重（LBW），发病率和 与未感染艾滋病毒的妇女所生婴儿的死亡率相比。虽然两者之间的联系 LBW和儿童存活率下降已经得到了很好的研究，将艾滋病毒或ART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 一个正在进行的、特征明确的女性艾滋病毒感染者队列，参加了一项数据驱动的持续质量试验 在刚果金沙萨采取干预措施，改善抗逆转录病毒疗法的长期效果;我们的具体 重点是艾滋病毒相关的炎症，免疫激活，和微生物群落的背景下， 一组600名接受抗逆转录病毒治疗的艾滋病毒感染妇女和600名艾滋病毒阴性对照沿着， 将招募艾滋病毒暴露的未感染（HEU）和艾滋病毒未暴露（HU）婴儿，并通过 分娩和产后长达12个月，以确定艾滋病毒/抗逆转录病毒疗法如何诱导胎盘功能障碍（目标1）或 微生物生态失调（目标2）调节LBW和随后的婴儿死亡率的风险。使用生物 从这些妇女获得的标本，我们将记录组织病理学胎盘异常（例如， 坏死）并测量炎症、免疫活化和微生物易位的标志物水平。我们 还将使用先进的微生物组和病毒组工具包，包括机器学习和生态系统建模 评估这些实体与炎症和LBW之间关联的方法，以及计算机测试 从功能分析中得出的无数机械假说。我们期望这些工作的完成 互补的目的将提供与增加的风险相关的生物学机制的见解， 暴露于艾滋病毒的婴儿中的低出生体重。这一见解最终可以确定最佳的艾滋病毒治疗或护理 怀孕WLH的模式：促进孕产妇健康，预防艾滋病毒母婴传播， 最大限度地提高婴儿存活率。