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

项目3摘要/摘要 接触母体艾滋病毒感染通过复杂的社会和生物交叉影响儿童的发育 小路。据报道，在认知、注意力、处理速度和执行功能方面得分较低 对于感染艾滋病毒的未感染(HEU)儿童与未感染艾滋病毒(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免疫激活，以及系统性慢性 早期感染引起的炎症，特别是巨细胞病毒(CMV)，可能有助于 儿童的神经发育缺陷。巨细胞病毒引起深刻的免疫激活和炎症 感染，并与生长较差，运动功能受损和增加的发病率有关 HEU儿童和艾滋病毒携带者儿童(CLHIV)。东非儿童在生命早期就感染了巨细胞病毒，40%-60% 3个月龄感染HEU和HUU。与HUU相比，HEU儿童感染CMV的时间更早， 持续几个月的系统性CMV病毒血症，尽管这对 目前还不清楚情况的发展。鉴于有大量数据将早期感染和炎症联系起来 神经发育延迟，以及大脑发育关键年龄的巨细胞病毒的高炎症效应， 我们建议调查早期获得CMV和控制不佳的CMV病毒血症的假设 HEU导致慢性炎症和免疫激活，从而导致生长发育的变化。 我们将利用现有的关于肯尼亚HEU和HUU的纵向出生队列研究，在该研究中，登记和 随访从妊娠晚期开始，产后持续2年，集中收集 标本和临床数据。跟踪将延长2年，以使详细和敏感的 4岁时对多个神经发育领域的评估。在目标1中，我们将确定 4岁婴儿巨细胞病毒感染与神经发育的关系在目标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，我们将进行中介分析，以询问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 了解早期感染和免疫侮辱对长期儿童的影响 并将为改善神经发育的干预措施的战略发展提供信息 HEU儿童的结局。

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.