Gestational and Lactational Exposure to HIV Tri-Combo Therapy Associated with Sex and Dose Dependent Changes in Inflammatory Cytokine Profiles, Intestinal Permeability, and Villi Morphology in Adult Rat Offspring

Yaswanthi Yanamadala¹Kuppan Gokulan¹Kumari Karn¹Vicki Sutherland²Helen Cunny²Janine Santos²Kelly Davis³Sangeeta Khare^1*

• ¹National Center for Toxicological Research (FDA), Jefferson, United States
• ²Division of Translational Toxicology,, National Institute of Environmental Health Sciences,, Research Triangle Park, NC 27709, United States
• ³Toxicologic Pathology Associates, 3900 NCTR Rd,, Jefferson, AR 72079, United States

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, Lamivudine). These changes may be driven by either the immune system and intestinal barrier integrity or potentially impact them. In this study, we further investigated the long-term effects of perinatal TC-ART exposure on intestinal permeability, cytokine profiles and intestinal mucosa morphology. We observed statistically significant sex-dependent differences, with male offspring exhibiting reduced weight gain, a dichotomy in low and high dose for inflammatory cytokines (IL-5, IL-7, 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 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. 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.