Abstract
People living with HIV (PLHIV) are at a higher risk of having cerebrocardiovascular diseases (CVD) compared to HIV negative (HIV
) individuals. The mechanisms underlying this elevated risk remains elusive. We hypothesize that HIV infection results in modified microRNA (miR) content in plasma extracellular vesicles (EVs), which modulates the functionality of vascular repairing cells, i.e., endothelial colony-forming cells (ECFCs) in humans or lineage negative bone marrow cells (lin
BMCs) in mice, and vascular wall cells. PLHIV (N = 74) have increased atherosclerosis and fewer ECFCs than HIV
individuals (N = 23). Plasma from PLHIV was fractionated into EVs (HIV
) and plasma depleted of EVs (HIV PL
). HIV
, but not HIV PL
or HIV
(EVs from HIV
individuals), increased atherosclerosis in
mice, which was accompanied by elevated senescence and impaired functionality of arterial cells and lin
BMCs. Small RNA-seq identified EV-miRs overrepresented in HIV
, including let-7b-5p. MSC (mesenchymal stromal cell)-derived tailored EVs (TEVs) loaded with the antagomir for let-7b-5p (miRZip-let-7b) counteracted, while TEVs loaded with let-7b-5p recapitulated the effects of HIV
in vivo. Lin
BMCs overexpressing
(a let-7b-5p target gene) lacking the 3'UTR and as such is resistant to miR-mediated regulation showed protection against HIV
-induced changes in lin
BMCs in vitro. Our data provide a mechanism to explain, at least in part, the increased CVD risk seen in PLHIV.
