Our findings collectively suggest that increased levels of EVs bearing molecules of B-cell immune activation, such as CD40, TNF-RII, IL-6Rα, and immunomodulatory molecules (PD-L1) may affect B-cell lymphomagenesis years prior to an AIDS-NHL diagnosis and thus, could help identify key molecules for diagnosis, immune escape, and other molecular factors associated with lymphoma initiation/development. This evidence concerns the gene CD40 and non-Hodgkin lymphoma.