Influence of fetal antiretroviral exposure on gut microbiota, systemic inflammation and neurodevelopment in infants exposed to HIV

据报道，在婴儿期和儿童早期， 与未暴露于艾滋病毒的对应者相比，在子宫内暴露于艾滋病毒但未感染（iHEU）， 抗逆转录病毒治疗（ART）方案可能会增加风险。宫内暴露于蛋白酶 与非PI抑制剂相比，PI抑制剂（PI）与语言和社会情感发展较差有关， 含有iHEU中的方案。目前，世界卫生组织（WHO）推荐度鲁特韦（DTG）， 一种整合酶链转移抑制剂（IGI），作为妊娠期间优选ART方案的组分。 胎儿暴露于INSTIs是否与iHEU中的神经发育延迟有关还不清楚 研究了在成人中，基于PI的方案的给药与肠道微生物群的改变有关， 与基于INSTI的方案相比，全身性炎症。然而，目前尚不清楚胎儿暴露是否仅 也会产生类似的效果。由于生命早期肠道微生物组和免疫激活已经 被证明对免疫成熟和认知功能的发展至关重要， 与神经发育的关联，关键是要探讨胎儿暴露于不同的 母体ART方案、早期肠道微生物组组成和功能、全身性炎症和 iHEU中的神经发育。我们假设早期生活肠道微生物群落及其功能 iHEU之间的差异在于胎儿暴露于母体PI与INSTI方案，导致差异 增加全身性炎症。我们希望这种改变与婴儿神经发育结果平行， 即使抗逆转录病毒药物暴露仅限于子宫内时期。我们将利用ART的监测 在儿科艾滋病毒/艾滋病队列研究（PHACS）网络中进行的毒性（SMARTT）研究， 严格的前瞻性收集数据，神经发育测试，以及一个样本库， 在200名iHEU SMARTT参与者的队列中解决我们的假设，具体目标如下： 具体目标1：通过以下方法评价iHEU中胎粪微生物组的多样性、组成和功能： 孕妇在怀孕期间接受抗逆转录病毒治疗。 具体目标2：评价母体抗逆转录病毒治疗iHEU的全身炎症水平 怀孕期间的养生 具体目标3：评估胎粪微生物组、全身性炎症和 iHEU中的神经发育。 拟议的项目将提供关键的初步数据，以设计进一步的调查和干预措施， iHEU中可修改的生物领域，可以告知这种增长的神经发育健康 人口，以及在怀孕期间的ART指南，这可能最终导致发病率下降， iHEU，或怀孕期间接触抗逆转录病毒药物的其他婴儿群体。

Higher risk of poor neurodevelopment during infancy and early childhood has been reported among infants who are HIV exposed in utero but uninfected (iHEU) compared to their HIV unexposed counterparts, and both HIV and antiretroviral therapy (ART) regimens may contribute to the increased risk. In utero exposure to protease inhibitors (PI) has been linked to poorer language and social-emotional development compared to non-PI- containing regimens in iHEU. Currently, the World Health Organization (WHO) recommends dolutegravir (DTG), an integrase strand transfer inhibitor (INSTI), as a component of a preferred ART regimen during pregnancy. Whether fetal exposure to INSTIs is associated with neurodevelopment delays among iHEU has not been well studied. In adults, administration of PI-based regimens has been linked to altered gut microbiota and increased systemic inflammation compared to INSTI-based regimens. However, it is unknown whether fetal exposure only to these regimens could provoke similar effects. As early life gut microbiome and immune activation have been shown to be crucial for development of immune maturation and cognitive functions, alongside recent descriptions of associations with neurodevelopment, it is pivotal to explore associations between fetal exposure to different maternal ART regimens, early life gut microbiome composition and function, systemic inflammation and neurodevelopment among iHEU. We hypothesize that early life gut microbial communities and their function differ among iHEU by fetal exposure to maternal PI- versus INSTI-based regimens, leading to differential increases in systemic inflammation. We expect such alterations to parallel infant neurodevelopmental outcomes, even when ARV exposure is limited to the in utero period. We will leverage the Surveillance Monitoring for ART Toxicities (SMARTT) study within the Pediatric HIV/AIDS Cohort Study (PHACS) network, which provides rigorously prospectively collected data, neurodevelopmental testing, and a sample repository that will enable us to address our hypothesis in a cohort of 200 iHEU SMARTT participants with the following specific aims: Specific Aim 1: To evaluate meconium microbiome diversity, composition and function among iHEU by maternal antiretroviral regimen during pregnancy. Specific Aim 2: To evaluate levels of systemic inflammation among iHEU by maternal antiretroviral regimen during pregnancy. Specific Aim 3: To assess associations between meconium microbiome, systemic inflammation and neurodevelopment in iHEU. The proposed project will provide critical preliminary data to design further investigations and interventions of modifiable biological domains among iHEU that may inform neurodevelopmental health of this growing population, as well as ART guidelines during pregnancy, which might ultimately result in decreased morbidity of iHEU, or other populations of infants exposed to ARVs during pregnancy.