Combination biomarkers for preventing HIV and adverse birth outcomes in a South African pregnancy cohort: implications for infant health

在南非妊娠队列中预防艾滋病毒和不良出生结局的组合生物标志物：对婴儿健康的影响

• 批准号: 10382303
• 负责人: Heather Beryl Jaspan
• 金额: $ 32.55万
• 依托单位: CENTRE/AIDS PROGRAMME/RES/SOUTH AFRICA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-03 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10382303
• 关键词: 16S ribosomal RNA sequencing; Address; African; Age-Months; Anaerobic Bacteria; Anti-Retroviral Agents; Bacteria; Bacterial Vaginosis; Benefits and Risks; Biological; Biological Markers; Birth; Breast Feeding; Child; Child Health; Clinical Investigator; Clinical Trials; Collaborations; Communicable Diseases; Consent; Data; Development; Disadvantaged; Environment; Exposure to; Female genitalia; Fetal Development; Genital; Genitalia; Growth; HIV; HIV Infections; HIV risk; High Risk Woman; Homeostasis; Immunity; Immunologics; Immunology; Impairment; Incidence; Infant; Infant Health; Infection; Inflammation; Inflammatory; Inflammatory Response; Institutes; Insulin Resistance; Intervention; Lactation; Lactobacillus; Late pregnancy; Lead; Liquid substance; Measures; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolism; Metagenomics; Microbe; Mitochondria; Mucous Membrane; Natural Immunity; Neurologic; Outcome; Parents; Pharmaceutical Preparations; Plasma; Postpartum Period; Predisposition; Pregnancy; Pregnancy Outcome; Pregnant Women; Premature Birth; Premature Infant; Premature Labor; Preparation; Province; Research; Research Personnel; Risk; Risk Factors; Sampling; Scientist; Second Pregnancy Trimester; South African; Swab; Technology; Time; Toxic effect; Underrepresented Populations; Universities; Vagina; Visit; Woman; adipokines; adverse birth outcomes; antenatal; cervicovaginal; chemokine; cohort; cytokine; experience; fetal; glucose metabolism; high risk; inflammatory marker; inflammatory milieu; innovation; microbial; microbial community; microbiome; multiplex assay; natural Blastocyst Implantation; neonatal morbidity; neonate; pre-exposure prophylaxis; pregnant; prevent; recruit; reproductive tract; safety and feasibility; transmission process; vaginal fluid; vaginal microbiota

Abstract Young pregnant women are at extremely high risk for acquiring HIV in late pregnancy and postpartum. Although the precise mechanisms to explain the high risk of HIV during this time period is unknown, highly diverse vaginal microbial communities and elevated genital inflammation have been associated with increased HIV susceptibility among non-pregnant women. A balanced maternal inflammatory milieu and a Lactobacillus dominated vaginal microbial communities have long been associated with optimal pregnancy outcomes. However, untimely or excessive inflammatory response or diverse microbial communities in the vagina can lead to adverse birth outcomes and/or HIV acquisition in at risk women. With heightened risk of HIV in pregnancy and postpartum, pre-exposure prophylaxis (PrEP) is increasingly being used during these periods but the effects of maternal PrEP use on child health outcomes remains underexplored. Here, we propose to use two unique cohorts of HIV- uninfected pregnant women and their infants from Umlazi, KwaZulu-Natal, including those actively taking PrEP, to better understand their risk factors for adverse birth outcomes and HIV acquisition as well as neonatal morbidity. The specific aims are to: 1) assess whether vaginal microbial taxa or cytokines during gestation predict risk of preterm labor and delivery in women at high risk for HIV. 16S rRNA gene sequencing and multiplex bead arrays will be used to characterize the composition of vaginal microbial communities and soluble biomarkers of genital inflammation in cervicovaginal swabs and SoftCup fluids collected from women at ~12.5-21.5 weeks’ gestation and relate these to incident preterm labor and delivery; 2) determine whether increased vaginal microbial diversity and/or inflammation could explain the higher HIV risk during late pregnancy and early postpartum. Microbial communities and cytokines from cervicovaginal swabs and SoftCup fluids collected at 14- 28 weeks’ gestation will be compared with those collected late pregnancy (38–40 weeks’ gestation) and 14 and 26 weeks postpartum to identify potential drivers of increased susceptibility HIV infection during these periods; and 3) to determine the effects of antiretroviral exposure during gestation and breastfeeding on infant glucose metabolism and innate immunity. Using samples collected from HIV-unexposed infants at 6 weeks and 12 months of age, plasma adipokine and cytokine levels and markers of insulin resistance will be compared in antiretroviral (ARV)-exposed versus unexposed infants. The proposed research is innovative and will, for the first time, determine whether specific vaginal anaerobic microbes and associated inflammation can predict which women will deliver preterm or acquire HIV in our setting. Further, unique cohorts are available to examine the immunological and metabolic effects of maternal ARV use during pregnancy on infant health without HIV exposure, to inform risk-benefit analyses of maternal PrEP. This study has the potential to lead to more refined interventions to mitigate risks of adverse birth outcomes, HIV acquisition and neonatal morbidity.

抽象的 年轻孕妇在怀孕晚期和产后患HIV的风险极高。虽然 解释这段时间内HIV的高风险的确切机制未知，阴道高度多样 微生物群落和生殖器感染升高与HIV易感性提高有关 在非怀孕的妇女中。平衡的母校炎症环境和乳酸杆菌占主导的阴道 长期以来，微生物群落与最佳妊娠结局有关。但是，不合时宜地 过度炎症反应或阴道中的潜水微生物群落会导致不良出生 在风险妇女中获得结果和/或艾滋病毒。随着怀孕和产后艾滋病毒风险的升高， 在这些时期，越来越多地使用暴露前预防（PREP），但母亲的影响 对儿童健康结果的准备使用尚未得到充实。在这里，我们建议使用两个独特的艾滋病毒群体 未感染的孕妇及其来自夸祖鲁 - 纳塔尔邦Umlazi的婴儿，包括那些积极进行准备的孕妇 更好地了解他们的不良出生结果和艾滋病毒的风险因素以及新生儿 发病率。具体目的是：1）评估妊娠期间阴道微生物类群或细胞因子是否预测 艾滋病毒高风险的女性早产和分娩的风险。 16S rRNA基因测序和多珠 阵列将用于表征阴道微生物群落和固体生物标志物的组成 从约12.5-21.5周收集的宫颈阴道拭子和软箱流体中的生殖器炎症 妊娠并将其与事件早产和交付有关； 2）确定阴道是否增加 微生物多样性和/或炎症可以解释怀孕晚期和早期的较高的HIV风险 产后。从14-收集的宫颈阴道拭子和软箱流体的微生物群落和细胞因子 将妊娠28周与妊娠晚期（38-40周的妊娠）和14个和 产后26周，以确定在这些时期易感性HIV感染增加的潜在驱动因素； 3）确定妊娠和母乳喂养期间抗逆转录病毒暴露对婴儿葡萄糖的影响 代谢和先天免疫。使用6周和12 几个月大，血浆脂肪因子和细胞因子水平以及胰岛素抵抗的标志物将在 抗逆转录病毒（ARV）暴露与意外婴儿。拟议的研究具有创新性，将会 第一次，确定特定的阴道厌氧微生物和相关炎症是否可以预测 妇女将在我们的环境中提供早产或获得艾滋病毒。此外，可用于检查独特的队列 孕妇在怀孕期间使用ARV对婴儿健康的免疫学和代谢作用 暴露，以告知孕产妇准备的风险效益分析。这项研究有可能导致更精致的 减轻不良出生结果，艾滋病毒获取和新生儿发病率的干预措施。