Successful prevention of mother-to-child HIV transmission (PMTCT) programs have reduced the risk of infant HIV infection in South Africa from 8% in 2008 to an estimated 1.4% in 2015, resulting in an increasing population of HIV-exposed uninfected (HEU) children. However, the long-term effects of HIV and antiretroviral therapy (ART) exposure on the developing brain is not well understood. While HEU children perform better than their counterparts living with HIV, they continue to demonstrate greater neurodevelopmental delay than HIV-unexposed uninfected (HUU) children. As a result, neuroimaging studies have looked at the developing brain in this population, however there is little consensus about typical exposure related effects. In addition, it is unclear whether previously reported exposure-related results are directly related to in utero exposure to HIV, or indirectly via family and/or environmental factors. Research focused on newborns allows one to eliminate possible contributions from other factors, clarifying the influence of ART and HIV exposure on the developing brain. This dissertation employs neuroimaging and neurocognitive data in a well-characterized infant cohort to better understand the influence of maternal HIV infection on the uninfected brain. HEU infants were exposed to ART in utero between 3 and 9 months, allowing for the study of potential ART exposure effects of as well as HIV exposure. This dissertation will identify HIV and ART exposure effects on brain structure. In addition, the relationship between neonate brain structural outcomes and cognitive abilities at 9-12 months will be determined to identify potential functional consequences of early structural abnormalities. Chapter two presents an analysis of manually traced subcortical volumes in 120 unexposed uninfected (HUU) and exposed uninfected (HEU) neonates. HEU neonates demonstrated significantly reduced mean caudate volumes bilaterally and left mean putamen volumes relative to HUU neonates. Further analysis revealed the observed differences in basal nuclei volumes were related to duration of ART in utero. Infants exposed to ART throughout pregnancy had similar caudate and putamen volumes compared to their HU counterparts. While infants exposed to ART post conception (from 3 - 8 months in utero) had significantly smaller mean caudate volumes bilaterally, and a trending smaller left putamen volume compared to HUU infants. Chapter three examines the potential functional consequences of HIV/ART volumetric reductions. We modelled manually traced neonatal subcortical volumes with neuropsychological outcomes at 9 - 12 months. Among HUU infants, bilateral pallidum volumes predicted neuropsychological measures across all domains. All volumes, with the exception of bilateral thalamus and vermis, predicted the general quotient score in HUU infants. In contrast, among the HEU infants, volumes did not relate to neuropsychological outcomes with the exception of the caudate, putamen and vermis predicting locomotion scores in the preconception group. While no HIV exposure differences were present in neuropsychological domains, HEU infants recruit alternative subcortical structures compared to typically developing unexposed infants. Chapter four presents a DTI-tractographic analysis of white matter connections between subcortical structures manually traced. HEU demonstrate white matter alterations in two tracts - higher FA between right putamen and left thalamus and higher MD between caudate and thalamus on the right hemisphere. The WM alterations observed in HEU appear to be from roles of both HIV and ART exposure. In contrast to ART dependent subcortical grey matter reductions, the observed white matter alterations are independent of maternal treatment initiation. In addition, we also find associations between unaltered white matter connections and both maternal immune health and ART duration during pregnancy. These results suggest white matter is influenced to varying degrees by HIV and ART exposure, as well as maternal health in pregnancy. Chapter five looks at the possible functional consequences of the reported alterations in white matter integrity. We modelled white matter connections between manually traced neonatal subcortical volumes with neuropsychological outcomes at 9 - 12 months. Similar to chapter 3, within HUU infants, we observed a number of white matter connections predictive of neuropsychological outcomes across all domains. And almost no white matter tracts predicted neuropsychological measures in HEU infants. These results again point to HEU infants recruiting different pathways to perform basic tasks. In conclusion, the results documented in this thesis points to the influence of HIV exposure, ART duration and maternal immune health on fetal brain development. However, these factors impact grey and white matter differently. ART initiated pre-conception was protective of caudate volumes but did not protect two white matter connections, the WM tract between right thalamus and right caudate, and WM that between left thalamus and right putamen. Within HUU neonates, basal ganglia and cerebellar volumes and white matter connections predicted neuropsychological outcomes in late infancy. However, HEU infants did not demonstrate the same associations suggesting they utilize alternate pathways from their HUU peers. While there were no exposure related differences across neuropsychological domains, the long-term functional consequences of altered structural recruitment is unknown. Finally, this thesis adds to the body of literature that early ART in pregnancy is neuroprotective, and that HIV exposure related structural alterations are evident as early as 2 - 4 weeks after birth.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:uct/oai:localhost:11427/36668 |
| Date | 11 August 2022 |
| Creators | Ibrahim, Abdulmumin |
| Contributors | Holmes, Martha, Meintjes, Ernesta, Warton, Fleur |
| Publisher | Faculty of Health Sciences, Department of Human Biology |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Doctoral Thesis, Doctoral, PhD |
| Format | application/pdf |
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