Human Immunodeficiency Virus Impairs Reverse Chole

PLoS BIOLOGY Human Immunodeficiency Virus Impairs Reverse Cholesterol Transport from Macrophages Zahedi Mujawar1[, Honor Rose2[, Matthew P. Morrow1, Tatiana Pushkarsky1, Larisa Dubrovsky1, Nigora Mukhamedova2, Ying Fu2, Anthony Dart2, Jan M. Orenstein1, Yuri V. Bobryshev3, Michael Bukrinsky1*, Dmitri Sviridov2 1 The George Washington University, Washington, District of Columbia, United States of America, 2 Baker Heart Research Institute, Melbourne, Victoria, Australia, 3 University of New South Wales, Sydney, New South Wales, Australia Several steps of HIV-1 replication critically depend on cholesterol. HIV infection is associated with profound changes in lipid and lipoprotein metabolism and an increased risk of coronary artery disease. Whereas numerous studies have investigated the role of anti-HIV drugs in lipodystrophy and dyslipidemia, the effects of HIV infection on cellular cholesterol metabolism remain uncharacterized. Here, we demonstrate that HIV-1 impairs ATP-binding cassette transporter A1 (ABCA1)-dependent cholesterol efflux from human macrophages, a condition previously shown to be highly atherogenic. In HIV-1–infected cells, this effect was mediated by Nef. Transfection of murine macrophages with Nef impaired cholesterol efflux from these cells. At least two mechanisms were found to be responsible for this phenomenon: first, HIV infection and transfection with Nef induced post-transcriptional down-regulation of ABCA1; and second, Nef caused redistribution of ABCA1 to the plasma membrane and inhibited internalization of apolipoprotein A-I. Binding of Nef to ABCA1 was required for down-regulation and redistribution of ABCA1. HIVinfected and Nef-transfected macrophages accumulated substantial amounts of lipids, thus resembling foam cells. The contribution of HIV-infected macrophages to the pathogenesis of atherosclerosis was supported by the presence of HIV-positive fo