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 年轻孕妇在怀孕后期和产后感染艾滋病毒的风险极高。 解释这一时期艾滋病毒高风险的确切机制尚不清楚，阴道高度多样化 微生物群落和生殖器炎症加剧与艾滋病毒易感性增加有关 在非孕妇中，平衡的母体炎症环境和乳酸杆菌占主导地位的阴道。 然而，微生物群落长期以来一直与最佳妊娠结局相关。 阴道内过度的炎症反应或多样化的微生物群落可能导致不良分娩 妊娠期和产后有感染艾滋病毒哮喘风险的女性的结局和/或艾滋病毒感染情况， 在这些时期，暴露前预防 (PrEP) 的使用越来越多，但孕产妇的影响 PrEP 对儿童健康结果的应用仍未得到充分探索，我们建议使用两个独特的 HIV 队列。 来自夸祖鲁-纳塔尔省乌姆拉齐的未感染孕妇及其婴儿，包括积极服用 PrEP 的孕妇及其婴儿， 更好地了解不良出生结果、艾滋病毒感染以及新生儿的危险因素 具体目标是：1）评估妊娠期间阴道微生物分类群或细胞因子是否具有预测作用。 HIV 高危女性的早产和分娩风险。16S rRNA 基因测序和多重微珠。 阵列将用于表征阴道微生物群落的组成和可溶性生物标志物 约 12.5-21.5 周时从女性收集的宫颈阴道拭子和 SoftCup 液体中发现生殖器炎症 妊娠并将其与早产和分娩事件联系起来；2) 确定阴道是否增加； 微生物多样性和/或炎症可以解释妊娠晚期和早期艾滋病毒风险较高的原因 产后 14 点采集的宫颈阴道拭子和 SoftCup 液体中的微生物群落和细胞因子。 妊娠 28 周时将与妊娠晚期（妊娠 38-40 周）和 14 周时收集的数据进行比较 产后 26 周，以确定这些时期艾滋病毒感染易感性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血糖的影响 使用从 6 周和 12 周时未暴露于 HIV 的婴儿身上采集的样本。 月龄时，血浆脂肪因子和细胞因子水平以及胰岛素抵抗标志物将在 所提议的研究对于暴露于抗逆转录病毒（ARV）的婴儿与未暴露于抗逆转录病毒（ARV）的婴儿而言是创新的。 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哪些 此外，在我们的环境中，女性可能会早产或感染艾滋病毒。 母亲在怀孕期间使用抗逆转录病毒药物对未感染艾滋病毒的婴儿健康的免疫和代谢影响 暴露，为孕产妇 PrEP 的风险效益分析提供信息 这项研究有可能带来更精细的结果。 降低不良出生结局、艾滋病毒感染和新生儿发病风险的干预措施。