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

摘要 年轻孕妇在怀孕后期和产后感染艾滋病毒的风险极高。虽然 解释这一时期艾滋病毒高风险的确切机制是未知的，高度多样化的阴道。 微生物群落和生殖器炎症增加与艾滋病毒易感性增加有关 在未怀孕的女性中。平衡的母体炎症环境和主导阴道的乳杆菌 长期以来，微生物群落一直与最佳妊娠结局有关。然而，不合时宜或 过度的炎症反应或阴道内微生物群落的多样性会导致难产。 高危妇女的结局和/或艾滋病毒感染。随着怀孕和产后感染艾滋病毒的风险增加， 暴露前预防(PrEP)在这些时期越来越多地使用，但孕产妇的影响 Prep对儿童健康结果的使用仍未得到充分探索。在这里，我们建议使用两个独特的艾滋病毒队列- 来自夸祖鲁-纳塔尔乌姆拉齐的未感染孕妇及其婴儿，包括积极接种PrEP的人， 为了更好地了解他们的不良生育结局、艾滋病毒感染以及新生儿的危险因素 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能预测 艾滋病毒高危妇女早产和分娩的风险。16S rRNA基因测序与多重珠 将使用阵列来表征阴道微生物群落的组成和可溶的生物标志物 妊娠12.5-21.5周妇女宫颈阴道拭子和软杯液中的生殖器炎症 并将这些与早产和分娩事件联系起来；2)确定阴道增加 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。从宫颈阴道拭子和软杯液中采集的微生物群落和细胞因子 28周的妊娠将与收集的妊娠晚期(38-40周)和14周和14周进行比较。 产后26周，以确定在此期间艾滋病毒感染易感性增加的潜在驱动因素； 3)确定孕期和哺乳期接触抗逆转录病毒对婴儿血糖的影响 新陈代谢和先天免疫。使用从6周和12周未接触艾滋病毒的婴儿身上收集的样本 月龄，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 接触抗逆转录病毒(ARV)的婴儿与未接触的婴儿相比。拟议的研究是创新的，将为 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 在我们的环境中，妇女将早产或感染艾滋病毒。此外，还提供了独特的队列来检查 孕妇孕期使用抗逆转录病毒病毒对无HIV婴儿健康的免疫和代谢影响 暴露，为孕产妇PrEP的风险-收益分析提供信息。这项研究有可能导致更精致的 采取干预措施，减少不良分娩结局、感染艾滋病毒和新生儿发病率的风险。

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.