Abstract 21362: The Combination Antiretroviral Therapy (cart) Inhibits Efferocytosis-Related Gene Expression via Activating P90rsk and Accelerates Atherosclerosis

Background: Increased incidence of cardiovascular disease (CVD) in HIV patients has been established, but the consequence of anti-HIV therapies in CVD is unclear. The activation of p90RSK in endothelial cells is a critical event in atherosclerosis, but its role in macrophage is unknown. Hypothesis: macrophage p90RSK plays a role in anti-HIV drug-induced CVD and atherosclerosis. Methods and Results: In macrophages, efferocytosis-related signaling was upregulated and inflammatory gene expression was down-regulated in a p90RSK activity-dependent manner. Using Lysm-Cre dominant negative (DN) p90RSK transgenic mice in LDLR-/- background fed a high-cholesterol diet, we found that p90RSK activation increases plaque formation, inducing pro-atherogenic phenotypes and enhancing M1 polarization. Every cART regimen we tested, except backbone regimen, activated macrophage p90RSK, reduced efferocytosis, and increased M1-type related gene expression. In human, peripheral monocytes were isolated from HIV infected individ...