Highly active antiretroviral therapy drugs inhibit in vitro cholesterol efflux from human macrophage-derived foam cells

We previously reported that HIV protease inhibitor ritonavir could inhibit cholesterol efflux and induce endothelial dysfunction. In this study, we further determined the effects and molecular mechanisms of a clinically relevant combination of highly active antiretroviral therapy (HAART) drugs on in vitro cholesterol efflux from human macrophage-derived foam cells. Foam cells derived from human monocyte cell line (THP-1) and periphery blood mononuclear cells (PBMCs) treated with HAART drugs including stavudine, didanosine and indinavir individually or in combination of 3 drugs (3-plex), followed by initiation of cholesterol efflux with apolipoprotein A-I (apoA-I). Clinically relevant concentrations of HAART 3-plex significantly reduced cholesterol efflux in foam cells derived from THP-1 and PBMCs. HAART 3-plex significantly reduced intracellular cholesterol transport molecule caveolin-1, while increased superoxide anion production in THP-1 foam cells as compared with controls. Furthermore, mitochondrial membrane potential was significantly reduced, while the expression of NADPH oxidase subunits p67phox was increased in HAART 3-plex-treated macrophages. Consequently, antioxidants including ginsenosides Rb1 and Rg1, S-allyl cysteine sulphoxide, simvastatin and vitamin E significantly abolished HAART 3-plex-induced inhibition of cholesterol efflux. Therefore, HAART drugs significantly inhibit cholesterol efflux from human macrophage-derived foam cells through down-regulation of caveolin-1 and increase of oxidative stress.