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

项目3概要/摘要 暴露于母亲艾滋病毒感染通过复杂的交叉社会和生物影响儿童的发展 途径。据报道，认知、注意力、处理速度和执行功能的得分较低 与未感染艾滋病毒的同龄人相比，未感染艾滋病毒的儿童（HEU）。越来越多的证据 表明在子宫内暴露于母体HIV相关的免疫激活，以及全身慢性 早期获得性感染的炎症，特别是巨细胞病毒（CMV），可能有助于 儿童神经发育缺陷。巨细胞病毒引起严重的免疫激活和炎症， 感染，并与生长不良，运动功能受损， 高浓缩铀儿童和感染艾滋病毒的儿童。东非儿童在生命早期获得CMV，40-60% 3个月大时感染高浓缩铀和呼肠孤的儿童。与HUU相比，HEU儿童更早获得CMV， 经历了持续数月的系统性CMV病毒血症，尽管这对 目前发展尚不清楚。鉴于大量的数据将早期感染和炎症联系起来， 神经发育延迟，以及CMV在大脑发育关键年龄的过度炎症效应， 我们建议研究以下假设： 高浓缩铀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高浓缩铀和高浓缩铀纵向出生队列研究， 随访从妊娠晚期开始，持续产后2年，并进行密集收集 标本和临床数据。随访将延长2年，以便详细和敏感地 4岁时多个神经发育领域的评估。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系。在目标2中，我们将评估 母婴免疫激活和炎症对4岁儿童神经发育的影响。 最后，我们将进行调解分析，以询问炎症和免疫激活的机制 导致HEU和HUU儿童的神经发育缺陷（目的3）。这些研究将提供更好的 了解早期感染和免疫损伤如何导致儿童长期 神经发育，并将告知干预措施的战略发展，以改善神经发育 高浓缩铀儿童的结果。

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.