HIV-infected subjects are at high risk of developing atherosclerosis, in part due to virus-induced impairment of HDL metabolism. Here, using as a model of HIV infection the NOD.Cg-Prkdc(scid)IL2rg(tm1wj1)/SzJ (NSG) mice humanized by human stem cell transplantation, we demonstrate that LXR agonist TO901317 potently reduces viral replication and prevents HIV-induced reduction of plasma HDL. These results establish that humanized mice can be used to investigate the mechanisms of HIV-induced impairment of HDL formation, a major feature of dyslipidemia associated with HIV-1 infection, and show potential benefits of developing LXR agonists for treatment of HIV-associated cardio-vascular disease. (C) 2012 Elsevier Inc. All rights reserved.