Cognitive function in HIV-exposed uninfected children in rural Zimbabwe

撒哈拉以南非洲地区三分之二的儿童没有充分发挥他们的潜力，这意味着他们在学校表现不佳，成年后智商较低，就业前景也较差。找出潜在的原因将使我们能够及早干预，以促进他们的大脑发育、学习和生活机会。全球有1500万儿童暴露于艾滋病毒，未感染，即HEU，这意味着他们的母亲感染了艾滋病毒，但他们自己避免感染艾滋病毒。这些艾滋病毒阳性母亲所生的艾滋病毒阴性儿童与艾滋病毒阴性母亲所生的儿童相比，在2岁时的儿童发育较差，但我们不知道原因。我们一直在跟踪津巴布韦农村的一大群儿童，从他们出生开始，我们的结果显示，7岁的HEU儿童的智力测试分数仍然低于未感染艾滋病毒的儿童。我们现在想了解受影响的大脑功能的范围，了解为什么这种差异在学龄阶段仍然存在，并了解早期生活干预一揽子措施（提高2岁时的考试成绩）是否对10岁的高智商儿童有持续的好处。我们将对10岁儿童的大脑功能进行详细的测试，通过一系列的测试和智力游戏，对他们的语言技能进行评估，并对行为和心理健康问题进行问卷调查。在一些儿童中，我们将测量他们的脑电模式，使用一顶戴在头上的帽子，用电线连接到电脑上。在做心理测试的同时，通过测量大脑不同部位的电模式，我们可以直接比较HEU和未接触艾滋病毒的儿童的大脑功能。然后，我们将探讨HEU儿童认知能力下降的可能原因。首先，我们认为接触艾滋病毒会破坏肠道和大脑之间的一些身体交流。这部分是通过被称为代谢物的化学物质发生的，代谢物是由肠道细菌产生的，并受饮食的影响。我们已经证明，HEU儿童的肠道细菌类型与未接触艾滋病毒的儿童不同，这可能会影响他们产生的代谢物，进而影响大脑发育的方式。HEU儿童也有过度的炎症（身体对感染或损伤的反应），这可能会损害正在发育的大脑。我们将使用储存的血液样本（在这些孩子18个月大时收集）来比较代谢物、炎症和神经细胞损伤的标志物。其次，我们认为儿童的环境会影响他们的大脑发育方式，因此我们将收集儿童的生活、照顾者的养育和家庭情况的信息，以比较HEU和未接触艾滋病毒的儿童的生活条件。最后，我们将看到，在高浓血症儿童出生后的头2年，对他们10岁时的认知能力是否有长期的好处。这些儿童在生命早期被随机分配（就像抛硬币一样），是否接受营养补充剂，是否改善家庭用水、环境卫生和个人卫生（WASH）。当我们在两岁时评估他们的大脑发育时，同时接受营养补充剂和改进的WASH的HEU儿童的测试成绩要好得多。现在我们想看看这种效果是否会持续10年，以及这些干预措施是否会通过改善肠道沟通和为大脑提供营养的方式而起作用。如果我们发现营养和讲卫生干预措施在10岁时仍有益处，这就为在所有艾滋病毒暴露儿童中推广这些策略提供了强有力的证据。如果我们看到的早期生活的好处不能持续，我们需要寻找新的方法。无论如何，该项目将发现需要解决的早期生活因素，以确保所有儿童都能成为健康和有生产力的成年人。

Two-thirds of children in sub-Saharan Africa do not develop to their full potential, meaning they will do less well at school, have lower adult IQ and poorer job prospects. Identifying the underlying reasons would allow us to intervene early to enhance their brain development, learning and life chances. 15 million children globally are HIV-exposed uninfected, or HEU, meaning they were born to mothers with HIV infection, but avoided being infected with HIV themselves. These HIV-negative children, born to HIV-positive mothers, have poorer child development at 2 years of age compared to children born to HIV-negative mothers, but we do not know why. We have been following a large group of children in rural Zimbabwe from birth, and our results show that 7 year old HEU children continue to have lower intelligence test scores than HIV-unexposed children. We now want to understand the range of brain functions that are affected, understand why this difference is still seen at school-age, and see whether an early life package of interventions (which improved test scores at age 2yrs) have a sustained benefit for HEU children by age 10 years. We will do detailed testing of children's brain function at age 10, through a range of tests and puzzles, an assessment of their language skills, and questionnaires about behavioural and mental health problems. In some children, we will measure their brain electrical patterns using a cap placed on the head with wires linked to a computer. By measuring electrical patterns in different parts of the brain while doing psychological tests, we can directly compare how the brain functions in HEU and HIV-unexposed children.We will then explore possible reasons for reduced cognition in HEU children. First, we believe HIV exposure disrupts some of the body's communication between the gut and the brain. This occurs partly through chemicals called metabolites which are produced by gut bacteria and are influenced by diet. We have shown that the types of gut bacteria in HEU children are different to HIV-unexposed children, and this may affect the metabolites they make, which in turn influences the way the brain develops. HEU children also have excess inflammation (the body's response to infection or injury) which may damage the developing brain. We will use stored blood samples (collected when these children were 18 months old) to compare metabolites, inflammation and markers of damage to nerve cells. Second, we believe the child's environment influences the way their brain develops, so we will collect information about the child's life, their caregiver's nurturing, and their household situation, to compare the living conditions of HEU and HIV-unexposed children. Finally, we will see whether a package of interventions, which were delivered to HEU children in the first 2 years of life, has a long-lasting benefit on their cognition at age 10 years. These children were randomised (like the flip of a coin) in early life to receive nutritional supplements or not, and improvements in household water, sanitation and hygiene (WASH) or not. HEU children who received both the nutritional supplements plus the improved WASH had much better test scores when we assessed their brain development at 2 years of age. Now we want to see if this effect lasts to 10 years and whether these interventions might have worked by improving the way the gut communicates and provides nutrients for the brain.If we find that nutrition and WASH interventions still have benefits at age 10, this provides powerful evidence for scaling up these strategies for all HIV-exposed children. If the early-life benefits that we saw are not sustained, we need to find new approaches. Either way, this project will discover factors in early life that need to be tackled to ensure that all children can become healthy and productive adults.