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

HIV感染儿童出生和神经发育结果的药物、微生物组和免疫决定因素

• 批准号: 10381032
• 负责人: Grace John-Stewart
• 金额: $ 431.95万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-09 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10381032
• 关键词: Address; Anti-Retroviral Agents; Area; Biological; Biological Factors; Biological Specimen Banks; Biometry; Birth; Brain; Child; Communication; Cytomegalovirus; Data; Detection; Development; Discipline of obstetrics; Enrollment; Ensure; Epidemiology; Evaluation; Exposure to; Funding; Grant; Growth; Gynecology; HIV; HIV Infections; HIV Seroprevalence; Hair; Human Milk; Immune; Immunology; Infant; Intervention; Kenya; Lead; Leadership; Life; Measurement; Mentors; Morbidity - disease rate; Mother-to-child HIV transmission; Neurocognition; Neurocognitive; Neuroimmune; Oligosaccharides; Outcome; Pediatrics; Perinatal; Pharmaceutical Preparations; Population; Prevention; Program Research Project Grants; Recording of previous events; Research; Research Design; Research Personnel; Role; Scientist; Site; Standardization; Structure; Training; Treatment Protocols; Viral Load result; antiretroviral therapy; cohort; design; fecal microbiome; gut microbiome; immune activation; in utero; insight; interest; meetings; microbiome; mortality; neurodevelopment; next generation; novel; prenatal exposure; programs; social factors

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.

在子宫内接触艾滋病毒但未被感染的儿童（高浓缩铀）已被证明生长受损， 神经发育迟缓，发病率和死亡率增加。关键是要确定这些机制， 差异本P01建议开展3个项目，以检查母体多鲁特韦（DTG）的影响 和病毒载量（项目1），微生物组和母乳母乳低聚糖（HMO）（项目2）， 母婴免疫激活和巨细胞病毒（项目3）对高浓缩铀儿童和未被 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），以确保 标准化的儿童神经发育评估和一致的分析方法。三个项目 解决翻译和机械重要性的领域。DTG在预防母婴传播中的使用目前正在扩大 没有关于儿童神经发育结果的数据。肠-脑连接和 神经免疫结果中的微生物组是越来越感兴趣的主题，但来自出生队列的数据有限。 研究已经证明了HEU和HUU婴儿肠道微生物组的早期差异。最后，标记 母体免疫激活和婴儿CMV时间的差异发生在HEU婴儿中， 生长和神经发育。这三个项目将涉及3个不同的出生队列， 由早期研究者领导的R 01研究：项目2和3将延长由R 01资助的高浓缩铀/高浓缩铀生产 纳入神经发育评估的队列（最初并非设计用于评估神经发育） 而项目1将招募一个新的高浓缩铀队列，并将该队列与对照R 01资助的HUU出生进行比较 队列。无论是否检测到HEU和HUU婴儿之间的差异，3个出生队列将 为生物因素对出生和神经发育结果的影响提供了新的见解。 P01总体目标： 1.建立一个包含三个项目和两个核心的P01结构，以协同评估影响 不同的生物因素对高浓缩铀/高浓缩铀出生队列的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，提供以下方面的标准化培训： 神经发育评估、技术输入和项目之间的一致分析方法。 3.实施共享管理核心来监督共享项目协调、管理， 和传播，召开年度会议，并促进三个项目之间的沟通。 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，重点是 优化HEU和HUU儿童结局，并推进探索生物学的协同科学议程 影响儿童结果的机制。P01将产生机械和转化的见解和影响 并为下一代美国和肯尼亚受训人员的合作发展提供机会。