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尚不清楚， 微生物群落和生殖器炎症的增加与HIV易感性的增加有关 在非怀孕妇女中。平衡的母体炎症环境和乳酸菌主导的阴道 长期以来，微生物群落与最佳妊娠结果有关。然而，不及时或 阴道内过度的炎症反应或多样化的微生物群落可导致不良分娩 结果和/或艾滋病毒感染的风险妇女。由于怀孕和产后感染艾滋病毒的风险增加， 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在儿童健康结果方面的应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Umlazi的未感染孕妇及其婴儿，包括积极服用PrEP的孕妇， 以更好地了解不良分娩结果和艾滋病毒感染的风险因素， 发病率具体的目的是：1）评估是否阴道微生物类群或细胞因子在妊娠期预测 艾滋病毒高危妇女的早产和分娩风险。16 S rRNA基因测序和多重微珠 阵列将被用来表征阴道微生物群落的组成和可溶性生物标志物， 在约12.5-21.5周时从女性中收集的宫颈阴道拭子和SoftCup液体中的生殖器炎症 妊娠并将这些与早产和分娩事件联系起来; 2）确定是否增加阴道分泌物 微生物多样性和/或炎症可以解释妊娠晚期和妊娠早期较高的艾滋病毒风险。 产后在14- 24小时收集的宫颈阴道拭子和SoftCup液体中的微生物群落和细胞因子 将妊娠28周与妊娠晚期（妊娠38-40周）和14和 产后26周，以确定在这些期间增加艾滋病毒感染易感性的潜在驱动因素; 以及3）确定妊娠期和哺乳期抗逆转录病毒暴露对婴儿血糖的影响 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中收集的样本， 月龄，血浆脂肪因子和细胞因子水平以及胰岛素抵抗标志物将在 抗逆转录病毒（ARV）暴露与未暴露的婴儿。建议的研究是创新的，将为 第一次，确定特定的阴道厌氧菌和相关的炎症是否可以预测 在我们的环境中，妇女会早产或感染艾滋病毒。此外，独特的队列可用于检查 母亲在怀孕期间使用抗逆转录病毒药物对无艾滋病毒婴儿健康免疫和代谢影响 暴露，告知产妇PrEP的风险-效益分析。这项研究有可能导致更完善的 * 采取干预措施，减少不良生育结果、艾滋病毒感染和新生儿发病的风险。

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.