Cholesterol efflux in HIV-associated atherosclerosis: mechanisms and targets.

Antiretroviral therapy (ART) has transformed HIV infection into a chronic, manageable condition; however, people living with HIV (PLWH) have an increased risk of atherosclerotic cardiovascular disease (ASCVD). Impaired cholesterol efflux due to dysfunction of macrophage lipid transporters and high-density lipoprotein (HDL) is an important mechanism in HIV-associated atherosclerosis. HIV Nef protein inhibits ATP-binding cassette transporter (ABC)A1-mediated cholesterol efflux via post-transcriptional downregulation, mislocalization, and enhanced degradation. Although ART partially improves macrophage and HDL functionality through viral suppression, cholesterol efflux impairment persists. Emerging therapies, including nuclear receptor agonists, apolipoprotein mimetics, and HDL-based nanoparticles, offer dual benefits by enhancing reverse cholesterol transport and reducing HIV replication. In this review, we explore the molecular mechanisms of HIV-induced cholesterol efflux impairment and potential therapies targeting ASCVD risk in HIV.