Higher risk of poor neurodevelopment during infancy and early childhood has been reported among infants who
are HIV exposed in utero but uninfected (iHEU) compared to their HIV unexposed counterparts, and both HIV
and antiretroviral therapy (ART) regimens may contribute to the increased risk. In utero exposure to protease
inhibitors (PI) has been linked to poorer language and social-emotional development compared to non-PI-
containing regimens in iHEU. Currently, the World Health Organization (WHO) recommends dolutegravir (DTG),
an integrase strand transfer inhibitor (INSTI), as a component of a preferred ART regimen during pregnancy.
Whether fetal exposure to INSTIs is associated with neurodevelopment delays among iHEU has not been well
studied. In adults, administration of PI-based regimens has been linked to altered gut microbiota and increased
systemic inflammation compared to INSTI-based regimens. However, it is unknown whether fetal exposure only
to these regimens could provoke similar effects. As early life gut microbiome and immune activation have been
shown to be crucial for development of immune maturation and cognitive functions, alongside recent descriptions
of associations with neurodevelopment, it is pivotal to explore associations between fetal exposure to different
maternal ART regimens, early life gut microbiome composition and function, systemic inflammation and
neurodevelopment among iHEU. We hypothesize that early life gut microbial communities and their function
differ among iHEU by fetal exposure to maternal PI- versus INSTI-based regimens, leading to differential
increases in systemic inflammation. We expect such alterations to parallel infant neurodevelopmental outcomes,
even when ARV exposure is limited to the in utero period. We will leverage the Surveillance Monitoring for ART
Toxicities (SMARTT) study within the Pediatric HIV/AIDS Cohort Study (PHACS) network, which provides
rigorously prospectively collected data, neurodevelopmental testing, and a sample repository that will enable us
to address our hypothesis in a cohort of 200 iHEU SMARTT participants with the following specific aims:
Specific Aim 1: To evaluate meconium microbiome diversity, composition and function among iHEU by
maternal antiretroviral regimen during pregnancy.
Specific Aim 2: To evaluate levels of systemic inflammation among iHEU by maternal antiretroviral
regimen during pregnancy.
Specific Aim 3: To assess associations between meconium microbiome, systemic inflammation and
neurodevelopment in iHEU.
The proposed project will provide critical preliminary data to design further investigations and interventions of
modifiable biological domains among iHEU that may inform neurodevelopmental health of this growing
population, as well as ART guidelines during pregnancy, which might ultimately result in decreased morbidity of
iHEU, or other populations of infants exposed to ARVs during pregnancy.
