Integrated proteomic and metabolomic biomarker profiling for understanding metabolic syndrome in pregnant women living with HIV on Tenofovir Disoproxil Fumarate/Lamivudine/Dolutegravir (TLD)

PROJECT ABSTRACT/SUMMARY Effective HIV treatment during pregnancy is critically important, both for the health of women living with HIV (PWHIV) and for prevention of perinatal HIV transmission. In the United States, Nigeria, and globally, Dolutegravir (DTG)- based antiretroviral therapy (ART) is being expanded as part of the preferred 1st-line ART

regimen, but emerging data show that DTG-based regimens are associated with excessive weight gain, treatment-emergent obesity, and metabolic dysfunction in PWHIV. Excessive weight gain and metabolic syndrome are critical during pregnancy because they increase the risk for pregnancy-related complications, such

as preterm birth, pre-eclampsia, gestational diabetes, fetal obesity, macrosomia, low birth weight, Cesarean delivery, and neonatal intensive care unit admissions. Yet, the mechanisms by which DTG-based ART-cause weight gain and metabolic syndrome in PWHIV are poorly understood, limiting our ability to fully deploy DTG-

based ART in this special population. To address this goal, we will leverage NIH infrastructure to conduct a prospective cohort study at 4 sites in two countries (US and Nigeria). Within this cohort, we will first identify cases of metabolic syndrome by examining the association between DTG-based ART regimens and metabolic

syndrome risk using the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria for pregnant and postpartum women living with HIV, and cohort-specific percentiles for waist circumference, systolic blood pressure, and serum glucose for their offspring. Subsequently, among PWHIV

diagnosed with metabolic syndrome (compared to controls), we will apply advanced integrated proteomic and metabolomic targeted profiling techniques to measure maternal proteins and metabolites (during pregnancy and postpartum) and umbilical cord blood proteins and metabolites to understand whether signature clusters of

proteins and metabolites differ between PWHIV diagnosed with metabolic syndrome (compared to selected controls), and if any signature clusters are associated with adverse maternal and child metabolic health. Biomarkers identified through integrated profiling would enhance the synergistic power of these ‘omics’

approaches to enable early detection of metabolic syndrome (even before clinical symptoms manifest), provide insights into treatment efficacy and potential adverse effects, and contribute to the development of personalized medicine strategies for PWHIV to guide the selection of interventions and therapies tailored to specific metabolite

profiles in clinical practice.