Immune‐Related Protein and Non‐Coding RNA Cargo of Extracellular Vesicles Participate in the Chronic Inflammation Induced by HIV Infection

Extracellular vesicles (EVs) promote intercellular communication, playing a key role in the secondary immune-related pathologies driven by chronic inflammation in people living with HIV (PLWH). To identify molecular components within large EVs (lEVs) from PLWH's plasma that may influence immune function and contribute to the pathological process. PLWH were classified using clinical data, cellular immunophenotyping, and plasma mediator profiling. lEVs were characterized using transcriptomic, proteomic, and interactome analysis. Their functional impact on immune cells was also assessed. PLWH showed signs of chronic basal inflammation. Compared to the control group, lEVs from PLWH carried the miR-4433b-3p, 31 long non-coding RNAs and 45 proteins differentially expressed. Key proteins-FBXO7, C3, SUGT1 and DTX3L-were linked to the miR-4433b-3p regulatory network, suggesting their involvement in inflammation. Interactome and pathway enrichment analysis associated these molecules to critical pathways, including NF-kappa B signalling and PI3K-AKT signalling. Finally, lEVs from PLWH more effectively modulated the production of inflammatory mediators in bystander immune cells. This study underscores the role of lEVs in shaping immune response during chronic HIV infection. By identifying specific molecular components, it provides valuable insights into potential therapeutic targets and candidate biomarkers for disease progression monitoring.