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

胎儿抗逆转录病毒暴露对暴露于 HIV 的婴儿的肠道微生物群、全身炎症和神经发育的影响

• 批准号: 10617395
• 负责人: Anna-Ursula Happel
• 金额: $ 17.78万
• 依托单位: UNIVERSITY OF CAPE TOWN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10617395
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adult; Affect; Anti-Retroviral Agents; Area; Bacteria; Biological; Birth; Breast Feeding; Data; Development; Emotional; Event; Exposure to; Guidelines; HIV; Health; Immune; Immune response; Immune system; Immunology; Individual; Infant; Inflammation; Inflammatory; Integrase; Intervention; Investigation; Language; Life; Link; Longevity; Measures; Meconium; Mediating; Monitor; Morbidity - disease rate; Mothers; Neurologic; Neurotransmitters; Outcome; Participant; Pediatric HIV/AIDS Cohort Study; Pharmaceutical Preparations; Play; Population; Pregnancy; Property; Protease Inhibitor; Recommendation; Regimen; Reporting; Research; Research Infrastructure; Research Training; Risk; Role; Sampling; Specimen; System; Testing; Treatment Protocols; Treatment-related toxicity; Vaginal delivery procedure; Vulnerable Populations; Woman; World Health Organization; antimicrobial; antiretroviral therapy; co-infection; cognitive function; cohort; comorbidity; cytokine; design; early childhood; fetal; fetal programming; gut bacteria; gut microbiome; gut microbiota; high risk; human data; immune activation; improved; in utero; infancy; inhibitor; insight; maternal microbiome; microbial; microbiome; microbiome composition; neurodevelopment; novel; postnatal; pre-exposure prophylaxis; prenatal; prenatal exposure; prospective; repository; social; systemic inflammatory response

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.

据报道，婴儿期和幼儿期神经发育不良的风险较高 与艾滋病毒相比，艾滋病毒暴露在子宫内，但未感染（iheu） 和抗逆转录病毒疗法（ART）方案可能导致风险增加。在子宫内暴露于蛋白酶 抑制剂（PI）与非PI-的语言和社会情感发展有关 在IHEU中包含方案。目前，世界卫生组织（WHO）推荐Dolutegravir（DTG）， 整合酶链转移抑制剂（Insti），是怀孕期间首选艺术方案的组成部分。 胎儿暴露于Instis是否与IHEU之间的神经发育延迟有关 研究。在成年人中，施用基于PI的方案已与肠道菌群改变并增加 与基于Insti的方案相比，系统性炎症。但是，尚不清楚胎儿是否仅暴露 这些方案可能会引起类似的影响。早期肠道微生物组和免疫激活一直是 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，探索胎儿暴露于不同的关联至关重要 孕产妇艺术方案，早期肠道微生物组组成和功能，全身性炎症和 IHEU之间的神经发育。我们假设早期生命肠道微生物群落及其功能 IHEU在胎儿暴露于母体PI与基于Insti的方案的不同之处，导致差异 系统性炎症增加。我们期望这种改变会平行婴儿神经发育结果， 即使ARV暴露仅限于子宫内。我们将利用监视监视的艺术 小儿艾滋病毒/艾滋病队列研究（PHACS）网络中的毒性（SMARTT）研究 严格的前瞻性收集数据，神经发育测试和样本存储库将使我们能够 在200个IHEU SMARTT参与者的队列中解决我们的假设，具有以下具体目标： 特定目的1：评估IHEU中胎粪微生物组的多样性，组成和功能 怀孕期间母亲抗逆转录病毒方案。 特定目的2：评估母体抗逆转录病毒IHEU之间的全身炎症水平 怀孕期间的方案。 特定目的3：评估胎粪微生物组，全身炎症和 Iheu的神经发育。 拟议的项目将提供关键的初步数据，以设计进一步的研究和干预措施 IHEU之间可修改的生物领域，可能为神经发育健康提供了这种增长 人口以及怀孕期间的艺术指南，最终可能导致发病率降低 IHEU或其他在怀孕期间暴露于ARV的婴儿种群。