The potential role of trained immunity in HIV-associated atherosclerotic cardiovascular disease: mechanisms and therapeutic implications.

People living with HIV (PLWH) exhibit a markedly elevated risk of developing atherosclerotic cardiovascular disease (ASCVD), a phenomenon not entirely attributable to conventional risk factors, thereby indicating the existence of an immune-mediated residual risk. Trained immunity may represent a critical underlying mechanism. This review explores the potential of HIV infection-induced trained immunity, examining its underlying mechanisms and its role in the pathophysiology of ASCVD. PubMed databases were searched for articles on the association between trained immunity and HIV infection and ASCVD. HIV triggers trained immunity through various mechanisms: viral proteins like Nef reprogram monocytes, microbial translocation via LPS activates the TLR4-NF-κB pathway, CMV co-infection boosts T-cell activity, and IgA-ADCP causes cross-activation. Some ART regimens (PI/INSTI) promote metabolic training, while CCR5 antagonists may counteract it. Clinical studies and the REPRIEVE trial show immune training markers (sCD14, sCD163) are linked to coronary issues and cardiovascular events, with statins unable to fully reduce monocyte/macrophage inflammation. Strategies include metabolic interventions, anti-IL-1β therapy, epigenetic drugs, optimizing ART, and nanobiological. Importantly, this review distinguishes between canonical innate trained immunity-driven by monocytes, macrophages, and vascular cells-and T-cell immunometabolic dysfunction, which, while coexisting in HIV infection, represents a distinct adaptive immune process. The former is our primary mechanistic focus for ASCVD. Trained immunity plays a pivotal role in the residual risk associated with HIV-associated ASCVD. From a mechanistic perspective, trained monocytes and macrophages contribute to foam cell formation by hindering cholesterol efflux. Concurrently, trained endothelial cells maintain vascular inflammation and enhance monocyte adhesion, collectively expediting the progression of plaque development. Elucidating the underlying regulatory mechanisms and undertaking intervention trials constitute prospective avenues for translational research.