Gestational and lactational exposure to HIV tri-combination therapy induces sex- and dose-dependent changes in inflammatory cytokine profiles, intestinal permeability, and villi morphology in adult rat offspring.

INTRODUCTION: Gestational antiretroviral therapy (ART) has significantly reduced the risk of vertical transmission of HIV, but concerns linger about its long-term effects on the fetal immune system and intestinal health. Our previous work has demonstrated dose-dependent changes in the fecal and mucosa-associated microbiome of adult rat offspring perinatally exposed to TC-ART (tri-combination ART: dolutegravir, abacavir, and lamivudine). These changes may either be driven by alterations in immune system and intestinal barrier integrity or potentially impact them.

METHODS: In this study, we further investigated the long-term effects of perinatal TC-ART exposure on intestinal permeability, cytokine profiles, and intestinal mucosa morphology.

RESULTS: We observed statistically significant sex-dependent differences, with male offspring exhibiting reduced weight gain, a dichotomous response between low and high dose for inflammatory cytokines [interleukin-5 (IL-5), IL-7, and IL-12], differential regulation for the mRNA expression of intestinal permeability-related genes (21 downregulated), and disrupted villous architecture, while females showed dose-dependent decreases in inflammatory cytokines [IL-17, IL-5, and macrophage colony-stimulating factor (M-CSF)]. In females, while some intestinal permeability genes were downregulated, the upregulation of other permeability genes suggests a compensatory mechanism to maintain the intestinal barrier function, indicating an overall milder response to TC-ART.

DISCUSSION: These findings suggest that perinatal exposure to TC-ART may have differential impacts on intestinal health, with females exhibiting a more adaptive response compared to males, highlighting the need for sex-specific considerations in evaluating long-term effects of ART.