Mechanistic intersection between placental vascular and newborn neuronal development

About This Grant

PROJECT SUMMARY More than one million children who are HIV-exposed but uninfected (HEU) are born to pregnant people with HIV (PPHIV) every year. HEU children have poorer early-life outcomes than their HIV-unexposed peers, including an increased risk of adverse neurodevelopmental outcomes. The pathophysiology of HEU neurodevelopmental outcomes is poorly understood. Mounting evidence suggests that altered placental gene expression may play a key mechanistic role, but the mechanisms have not been fully elucidated. A better understanding of the mechanisms of adverse developmental outcomes in HEU children is essential to improve the care of PPHIV and their offspring. Our overarching goal is to determine the effects of maternal HIV infection and specific antiretrovirals (ARVs) on placental and neural development, identify shared mechanisms of abnormal vascularity affecting both placenta and fetal brain, and how these perturbations impact HEU child neurodevelopment. Leveraging our ongoing multi-country birth cohort and linked placental biobank, we will perform spatial transcriptomics analysis, immunostaining, flow cytometry, and leverage a mouse model of pregnancy to determine which gene expression changes occur in the setting of maternal HIV and ARVs that might be linked to adverse neurodevelopmental outcomes. Innovation: Distinct advantages of our proposed research include 1) novel focus on the placenta-brain axis and the placenta as a source of adverse child health outcomes, 2) large multi-site cohort across HIV-affected regions of Africa and use of formalin-fixed samples, and 3) innovative methods to identify intervenable mechanisms. Investigators: Our interdisciplinary mPI team with expertise in HIV and birth cohorts (Bebell), placental immunology in HIV (Gray) and mouse models of ARVs (Serghides) paired with expertise in spatial transcriptomics (Arora), computational analysis (Shu), maternal and child health (Ngonzi, Kumbakumba) and perinatal pathology (Roberts, Mtshali) is well-poised to complete this work. Approach: We will leverage biobanked placental samples from mother-child dyads enrolled in mPI Bebell's (K23AI138856/ R01HD11232) and mPI Gray's (R01HD102050) birth cohorts, mPI Serghides' established mouse model of ARVs and HIV in pregnancy, and mPI Gray's established HIV immunology laboratory to elucidate mechanisms of HIV and ARV exposure on the placenta and neurodevelopment through via these Specific Aims: 1) investigate the impact of HIV and specific ARVs on placental spatial proteomic and transcriptomic expression differences, 2) compare quantitative and functional β-catenin, LEF-1 and FXIIIA1 expression between PPHIV and HU controls, and 3) assess endothelial network development in placenta and brain tissue during pregnancy and early life in HIV- and ARV-exposed mice. Identifying mechanisms HIV- and ARV-related placental abnormalities and adverse HEU child neurodevelopment and growth has great potential to improve child health outcomes by optimizing ARV selection in pregnancy and identifying and intervening early for children at risk of adverse growth and neurodevelopmental outcomes.