Extracellular vesicle miRNAs reflect treatment duration and inflammation state in long-term treated people living with HIV

Abstract Understanding persistent physiological dysregulations in HIV infection, including altered extracellular vesicle (EV) cargo, may improve our insight into HIV disease heterogeneity beyond virological suppression. We examined EV-associated microRNAs (miRNAs) in relation to immune dysregulation among people living with HIV (PLWH). We quantified the relative abundance of 20 EV-associated immunoregulatory miRNAs in plasma samples from 16 ART-naïve, 27 ART-treated PLWH, and 10 uninfected controls. Six miRNAs—miR-16-5p, miR-20a-5p, miR-142-3p, miR-146a-5p, miR-382-5p, and miR-615-5p showed substantial dysregulation across the three groups, with the ART-naïve group showing a > 20-fold decrease in median expression relative to uninfected controls ( p < 0.05). Interestingly, within the ART-treated group, we observed a heterogeneous distribution of the six miRNAs: one subgroup displayed high abundance similar to uninfected controls, while another mirrored ART-naïve profiles. Using a composite miRNA abundance score, high miRNA expressors had significantly longer duration of ART than low miRNA expressors (median 10 vs. 6 years; p = 0.0056) and lower circulating levels of IL-5, FGF-b, GM-CSF, and VEGF ( p < 0.05). These findings suggest heterogeneity among long-term treated PLWH, which is reflected in the EV-associated immunoregulatory miRNA signature. Understanding these nuances could provide novel markers for monitoring treatment and disease progression beyond viral load suppression.