Perinatal antiretroviral-associated cytokine and gut microbiota outcomes in deer mouse dams and their behaviorally diverse adult offspring

Abstract

Roll-out of tenofovir disoproxil fumarate/emtricitabine (TDF/FTC)-based pre-exposure prophylaxis (PrEP) for HIV prevention during pregnancy is increasing the number of infants perinatally exposed to antiretrovirals. Emerging evidence links perinatal antiretroviral (ART) and/or HIV exposure to later-life neurocognitive impairments, with oxidative stress, immune dysregulation and gut microbiota modification suggested as some of the major underlying role players. In human cohorts, disentangling the effects of exposure to maternal ART vs. maternal HIV on child development remains challenging. Thus, to address this gap, we investigated the impact of TDF/FTC on these biobehavioural outcomes in a controlled animal model. Using 60 female deer mice and their offspring, we assessed brain antioxidant defenses and immune signaling at 3-weeks-old and adulthood, gut microbiota composition at 3-weeks-old and adulthood, and nesting behavior during adulthood. Specifically, we sought to establish whether perinatal ART exposure alters oxidative stress, immune modulation, and gut microbiota composition and how these physiologies associate with adult psychobiological phenotypes, as reflected by nesting expression. Pregnancy and perinatal ART exposure significantly weakened brain antioxidant defenses and reduced brain tissue cytokine concentrations, while pregnancy also induced shifts in gut microbiota composition in female mice. Moreover, in offspring that exhibited orthogonal nesting behaviors in adulthood, perinatal ART exposure was distinctly associated with altered inflammatory signaling and gut microbiota composition. These findings suggest involvement of gut-immune-brain mechanisms as important modulators of the long-term impact of perinatal ART exposure on offspring neurobehavioral outcomes. This work also confirms the deer mouse as a valuable model for investigating naturalistic neurodevelopmental consequences of perinatal ART exposure.