HIV/ART, low birth weight, and mortality in HIV-exposed uninfected children: a translational mechanistic study

摘要 尽管艾滋病毒携带者孕妇终身三联抗逆转录病毒疗法(ART)的规模迅速扩大 低出生体重(LBW)、发病率和 与非艾滋病毒携带者所生婴儿的死亡率进行比较。尽管两者之间的关联 LBW和儿童存活率下降的关系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 持续的、特征良好的艾滋病毒感染妇女队列参加了一项数据驱动的持续质量试验 干预措施以改善刚果民主共和国金沙萨的抗逆转录病毒治疗的长期结果；我们的具体情况 重点关注艾滋病毒相关的炎症、免疫激活和微生物群落 普世艺术。接受抗逆转录病毒治疗的600名艾滋病毒携带者和600名艾滋病毒阴性对照妇女与他们的 将招募未感染艾滋病毒的婴儿(HEU)和未接触艾滋病毒的婴儿(HU)，并通过 分娩和产后12个月，以确定艾滋病毒/抗逆转录病毒治疗如何导致胎盘功能障碍(目标1)或 微生物失调(目标2)调节了低出生体重和随后的婴儿死亡的风险。使用生物 从这些妇女身上获得的标本，我们将记录组织病理胎盘异常(例如 并测量炎症、免疫激活和微生物易位的标志物水平。我们 还将使用具有机器学习和生态系统建模的尖端微生物组和病毒工具包 评估这些实体与炎症和LBW以及矽肺试验相关性的方法 从泛函分析中衍生出无数的机械假说。我们期望这些工作能够完成 互补的AIMS将提供对与增加的风险相关的生物学机制的洞察(S) 暴露在艾滋病毒感染的婴儿中的体重。这一洞察力最终可能确定最佳的艾滋病毒治疗或护理 孕期妇女生殖健康模式：促进产妇健康，防止艾滋病毒母婴传播， 最大限度地提高婴儿存活率。

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.