Drug, microbiome, and immune determinants of birth and neurodevelopmental outcomes in children with exposure to HIV infection

在子宫内暴露于艾滋病毒但未感染(HEU)的儿童已被证明发育受损， 神经发育迟缓，发病率和死亡率增加。为这些定义机制是至关重要的 不同之处。本P01建议进行3个项目，以检查母亲多洛替格韦(DTG)的影响 和病毒载量(项目1)、微生物组和母乳低聚糖(项目2)和 母婴免疫激活和巨细胞病毒(项目3)对HEU儿童和非HEU儿童结局的影响 HIV暴露(HUU)。这三个项目将使用一个共享的测量和分析核心(MA核心)来确保 标准化的儿童神经发育评估和统一的分析方法。三个项目 解决具有翻译和机械重要性的领域。DTG的使用目前正在PMTCT中扩大 计划，而且没有关于儿童神经发育结果的数据。肠脑连接及其在脑-神经系统中的作用 微生物群在神经免疫结果中的作用越来越引起人们的兴趣，来自出生队列的数据有限。 研究已经证实了HEU和HUU婴儿早期肠道微生物组的差异。最后，标记 HEU婴儿在母亲免疫激活和婴儿CMV时间上的差异可能会影响 生长和神经发育。这三个项目将涉及3个不同的出生队列，将利用3个正在进行的 由早期调查人员领导的R01研究：项目2和3将延长正在进行的由R01资助的HEU/HUU分娩 纳入神经发育评估的队列(最初不是为评估神经发育而设计) 虽然项目1将招募新的HEU队列，并将该队列与由R01资助的HUU出生进行比较 一群人。无论是否检测到HEU和HUU婴儿之间的差异，3个出生队列将 对生物因素对出生和神经发育结果的影响提供新的见解。 P01总体目标： 1.构建3个项目、2个核心的P01架构，协同评估影响 HEU/HUU出生队列中不同生物因素对出生和神经发育结果的影响。 2.实施共享的测量和分析核心，提供标准化的培训 神经发展评估、技术投入和项目间协调一致的分析方法。 3.实施共享管理核心，以监督共享项目的协调、管理、 和传播，召开年度会议，促进3个项目之间的沟通。 拟议的P01将凝聚一组早期和成熟的肯尼亚和美国调查人员，他们专注于 优化HEU和HUU儿童结局，推进探索生物学的协同科学议程 影响儿童结果的机制。P01将产生机械性和翻译性的见解和影响 并为下一代美国和肯尼亚学员的合作发展提供机会。

Children exposed to HIV in utero but who are not infected (HEU) have been shown to have compromised growth, neurodevelopmental delays, and increased morbidity and mortality. It is critical to define mechanisms for these differences. This P01 proposes to conduct 3 Projects to examine the influence of maternal dolutegravir (DTG) and viral load (Project 1), microbiome and breastmilk human milk oligosaccharides (HMOs) (Project 2) and maternal/infant immune activation and CMV (Project 3) on outcomes in HEU children and children who are not HIV-exposed (HUU). The three Projects will use a shared Measurement and Analysis Core (MA Core) to ensure standardized child neurodevelopmental evaluations and aligned analytic approaches. The three Projects address domains of translational and mechanistic importance. DTG use is currently expanding in PMTCT programs and there are no data on child neurodevelopmental outcomes. Gut-brain connections and the role of the microbiome in neuroimmune outcomes are topics of increased interest with limited data from birth cohorts. Studies have demonstrated early differences in gut microbiome of HEU and HUU infants. Finally, marked differences in maternal immune activation and infant CMV timing occur in HEU infants which could influence growth and neurodevelopment. The three Projects will involve 3 distinct birth cohorts that will leverage 3 ongoing R01 studies led by early-stage investigators: Projects 2 and 3 will extend ongoing R01-funded HEU/HUU birth cohorts (not originally designed to assess neurodevelopment) to incorporate neurodevelopmental assessment while Project 1 will enroll a new HEU cohort and compare this cohort to a comparator R01-funded HUU birth cohort. With or without detection of differences between HEU and HUU infants, the 3 birth cohorts will provide novel insights on the influence of biologic factors on birth and neurodevelopmental outcomes. Overall P01 Aims: 1. To build a P01 structure that involves 3 Projects and 2 Cores to synergistically evaluate the influence of distinct biologic factors on birth and neurodevelopmental outcomes in HEU/HUU birth cohorts. 2. To implement a shared Measurement and Analysis Core that provides standardized training on neurodevelopmental assessments, technical input, and aligned analytic approaches between Projects. 3. To implement a shared Administrative Core to oversee shared project coordination, administration, and dissemination, convene annual meetings and to facilitate communication between the 3 Projects. The proposed P01 will cohere a group of early and established Kenyan and US investigators focused on optimizing HEU and HUU child outcomes and advance a synergistic scientific agenda that probes biologic mechanisms influencing child outcomes. The P01 will yield mechanistic and translational insights and impact and provide opportunities for collaborative development of next-generation US and Kenyan trainees.