Cognitive function in HIV-exposed uninfected children in rural Zimbabwe
Lead Research Organisation:
Queen Mary University of London
Department Name: Sch of Medicine & Dentistry
Abstract
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.
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.
Technical Summary
Two-thirds of children in Africa fail to reach their academic potential. Multiple factors disrupt brain development, including exposure to maternal HIV in pregnancy. Despite avoiding infection, children who are HIV-exposed but uninfected (HEU) have impaired development by age 2yrs. We will now evaluate brain function in HEU children at age 10 years, define biological and psychosocial mechanisms underlying cognitive impairment, and explore long-term effects of an early-life intervention package on cognition.
We will leverage a cohort in rural Zimbabwe, who have been followed from birth, and are now 10yrs old. First, we will use a detailed test battery to compare cognitive processing, executive function and academic ability between HEU and HIV-unexposed children. In a subgroup, we will explore information processing and working memory using EEG neuroimaging.
Next, we will define biological and psychosocial pathways underlying cognitive impairment. We will evaluate the gut-brain axis by measuring metabolites, inflammatory mediators and markers of neuronal and glial disruption in stored plasma from age 18mo, and assess persistence of any perturbations in samples collected at age 10yrs. We will use an ecological systems approach to explore how positive and negative psychosocial factors, child mental health, wellbeing and behaviour differentially shape neurodevelopment in HEU and HIV-unexposed children.
Finally, we will evaluate the long-term effects of a randomised nutrition, water, sanitation and hygiene intervention package, which improved HEU child development by age 2yrs. We will evaluate 10yr cognitive outcomes by randomised trial arm, in an intention to treat analysis.
Our results will clarify the impact of HIV exposure on school-age cognitive function and define underlying mechanisms. If early-life interventions have long-term benefits, it provides a rationale for scale-up; if not, new approaches will be informed by our mechanistic insights.
We will leverage a cohort in rural Zimbabwe, who have been followed from birth, and are now 10yrs old. First, we will use a detailed test battery to compare cognitive processing, executive function and academic ability between HEU and HIV-unexposed children. In a subgroup, we will explore information processing and working memory using EEG neuroimaging.
Next, we will define biological and psychosocial pathways underlying cognitive impairment. We will evaluate the gut-brain axis by measuring metabolites, inflammatory mediators and markers of neuronal and glial disruption in stored plasma from age 18mo, and assess persistence of any perturbations in samples collected at age 10yrs. We will use an ecological systems approach to explore how positive and negative psychosocial factors, child mental health, wellbeing and behaviour differentially shape neurodevelopment in HEU and HIV-unexposed children.
Finally, we will evaluate the long-term effects of a randomised nutrition, water, sanitation and hygiene intervention package, which improved HEU child development by age 2yrs. We will evaluate 10yr cognitive outcomes by randomised trial arm, in an intention to treat analysis.
Our results will clarify the impact of HIV exposure on school-age cognitive function and define underlying mechanisms. If early-life interventions have long-term benefits, it provides a rationale for scale-up; if not, new approaches will be informed by our mechanistic insights.
