Extracellular vesicle-derived circRNA profiles from cART suppressed pregnant women living with HIV identifies interactome networks key to inflammation and viral latency

Pregnant people living with HIV (PLWH) experience a disparate risk of chronic non-AIDS-related morbidities (NAMs) during pregnancy compared to people without HIV infection. Extracellular vesicles (EV) are fundamental to both HIV pathogenesis and maternal-placental-fetal systemic intercellular networking. However, there is limited research addressing the intersection of EV cargo and HIV during pregnancy. In this study, plasma-derived EV small RNA (smRNA) in pregnant PLWH as compared to pregnant people living without HIV (PLWoH) was examined through low-input RNA sequencing (Illumina PE150). Differential expression analysis identified significant alterations of EV circRNA levels for pregnant PLWH as compared to pregnant PLWoH. Novel interactome networks (circRNA-miRNA-gene and circRNA-protein) were generated from these differentially expressed EV circRNAs. Gene set enrichment analysis revealed physiological pathways influential to HIV reservoir establishment, latency, replication, immune activation, immunosenescence, as well as maternal-placental-fetal immune cross talk. These findings suggest that EV circRNA-mediated regulatory mechanisms may contribute to HIV persistence, inflammation, and immune modulation in pregnancy.