The effect of cytomegalovirus, inflammation, and immune activation on neurodevelopment in children exposed to maternal HIV infection

巨细胞病毒、炎症和免疫激活对母亲 HIV 感染儿童神经发育的影响

• 批准号: 10381037
• 负责人: Jennifer Ann Slyker
• 金额: $ 89.26万
• 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/10381037
• 关键词: 4 year old; Affect; African; Age; Age-Months; Area Under Curve; Attention; Biological; Biological Assay; Birth; Blood; Brain; Cells; Child; Child Development; Child Malnutrition; Chronic; Clinical Data; Cognition; Cognitive; Cohort Studies; Complex; Containment; Cytomegalovirus; Cytomegalovirus Infections; Data; Development; Diagnosis; Enrollment; Enzyme-Linked Immunosorbent Assay; Exposure to; Feces; Flow Cytometry; Frequencies; Gene Expression Profile; Growth; Growth and Development function; HIV; HIV Infections; IL8 gene; Immune; Immunologics; Immunology procedure; Impairment; Infant; Infection; Inflammation; Inflammatory; Interleukin-1; Interleukin-6; Intervention; Kenya; Language; Lead; Life; Link; Measures; Mediation; Memory; Morbidity - disease rate; Motor; Mucous Membrane; Neurodevelopmental Deficit; Outcome; Pathway interactions; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Plasma; Postpartum Period; Pregnancy; Reporting; TNF gene; Third Pregnancy Trimester; Viral Load result; Viremia; Woman; cognitive function; cytokine; early experience; executive function; experience; follow-up; gut dysbiosis; gut microbiome; high dimensionality; immune activation; improved; in utero; infancy; inflammatory marker; innovation; microbiome; motor impairment; neurodevelopment; novel; pathogen; peer; processing speed; sample collection; single-cell RNA sequencing; social; systemic inflammatory response; therapy design; therapy development; transcriptome; transcriptome sequencing; transcriptomics

Project 3 Summary / Abstract Exposure to maternal HIV infection affects child development through complex intersecting social and biologic pathways. Lower scores for cognition, attention, processing speed, and executive function have been reported for HIV-exposed uninfected (HEU) children compared to HIV-unexposed (HUU) peers. Increasing evidence indicates that exposure to maternal HIV-associated immune activation in utero, as well as systemic chronic inflammation from infections acquired in early life, particularly cytomegalovirus (CMV), may contribute to neurodevelopmental deficits in children. CMV elicits profound immune activation and inflammation following infection, and has been associated with poorer growth, impaired motor functioning, and increased morbidity in HEU children and children living with HIV (CLHIV). East African children acquire CMV early in life, with 40-60% of HEU and HUU infected by 3 months of age. By contrast with HUU, HEU children acquire CMV earlier and experience persistent systemic CMV viremia for many months, although the consequences of this for development are currently unclear. Given the wealth of data linking early-life infections and inflammation to neurodevelopmental delays, and the hyper-inflammatory effect of CMV at a critical age for brain development, we propose to investigate the hypothesis that early acquisition of CMV and poorly-controlled CMV viremia in HEU lead to chronic inflammation and immune activation, which leads to changes in growth and development. We will leverage an existing longitudinal birth cohort study of HEU and HUU in Kenya in which enrollment and follow-up started in the third trimester of pregnancy and continued for 2 years postpartum with intensive collection of specimens and clinical data. Follow-up will be extended for 2 years to enable a detailed and sensitive assessment of multiple neurodevelopmental domains at 4 years of age. In Aim 1, we will determine the association between infant CMV infection and neurodevelopment at 4 years of age. In Aim 2, we will assess the impact of maternal and infant immune activation and inflammation on child neurodevelopment at 4 years of age. Lastly, we will conduct mediation analyses to interrogate mechanisms of inflammation and immune activation leading to neurodevelopmental deficits in HEU and HUU children (Aim 3). These studies will provide a better understanding of how early-life infections and immunologic insults contribute to long-term child neurodevelopment and will inform strategic development of interventions to improve neurodevelopmental outcomes in HEU children.

项目 3 摘要/摘要 孕产妇感染艾滋病毒会通过复杂的、交叉的社会和生物因素影响儿童发育 途径。据报道，认知、注意力、处理速度和执行功能得分较低 暴露于艾滋病毒的未感染儿童 (HEU) 与未暴露于艾滋病毒 (HUU) 的同龄人进行比较。越来越多的证据 表明在子宫内暴露于母体艾滋病毒相关的免疫激活，以及全身慢性 生命早期感染引起的炎症，特别是巨细胞病毒（CMV），可能会导致 儿童神经发育缺陷。 CMV 引发深度免疫激活和炎症 感染，并与生长较差、运动功能受损和发病率增加有关 HEU 儿童和艾滋病毒感染者 (CLHIV) 儿童。东非儿童在生命早期就感染巨细胞病毒，40-60% 3 个月龄时感染的 HEU 和 HUU。与 HUU 相比，HEU 儿童更早获得 CMV，并且 持续数月的系统性 CMV 病毒血症，尽管其后果 目前发展尚不清楚。鉴于有大量数据将早期感染和炎症与 神经发育迟缓，以及巨细胞病毒在大脑发育关键年龄的超炎症作用， 我们建议研究以下假设：早期获得 CMV 和控制不良的 CMV 病毒血症 高浓铀会导致慢性炎症和免疫激活，从而导致生长和发育的变化。 我们将利用肯尼亚现有的 HEU 和 HUU 纵向出生队列研究，其中入学率和 随访从妊娠晚期开始，持续2年，并进行密集收集 标本和临床数据。随访将延长2年，以实现详细而敏感的 4 岁时对多个神经发育领域进行评估。在目标 1 中，我们将确定 婴儿 CMV 感染与 4 岁时神经发育之间的关联。在目标 2 中，我们将评估 母婴免疫激活和炎症对 4 岁时儿童神经发育的影响。 最后，我们将进行中介分析来探究炎症和免疫激活的机制 导致 HEU 和 HUU 儿童神经发育缺陷（目标 3）。这些研究将提供更好的 了解生命早期感染和免疫损伤如何影响长期儿童 神经发育，并将为改善神经发育的干预措施的战略发展提供信息 HEU 儿童的结果。