Abstract
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. HIV-infected 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 foam cells in atherosclerotic plaques of HIV-infected patients. Stimulation of cholesterol efflux from macrophages significantly reduced infectivity of the virions produced by these cells, and this effect correlated with a decreased amount of virion-associated cholesterol, suggesting that impairment of cholesterol efflux is essential to ensure proper cholesterol content in nascent HIV particles. These results reveal a previously unrecognized dysregulation of intracellular lipid metabolism in HIV-infected macrophages and identify Nef and ABCA1 as the key players responsible for this effect. Our findings have implications for pathogenesis of both HIV disease and atherosclerosis, because they reveal the role of cholesterol efflux impairment in HIV infectivity and suggest a possible mechanism by which HIV infection of macrophages may contribute to increased risk of atherosclerosis in HIV-infected patients.
Highlights
Macrophage cells and cholesterol play a central role in the pathogenesis of two diseases, AIDS and atherosclerosis
A similar effect was observed in macrophages infected with two primary macrophage-tropic HIV-1 strains, Yu-2 and 92US660, indicating that impairment of cholesterol efflux is a general feature of HIV-1 replication in macrophages (Figure 1A)
At the time of analysis (21 d after infection), 80%–90% of the cells infected with ADA and Yu-2 viruses were p24þ, indicating that reverse transcription (RT) values in these infections reflected the amount of virus
Summary
Macrophage cells and cholesterol play a central role in the pathogenesis of two diseases, AIDS and atherosclerosis. Macrophages are among the main targets of HIV in the body, and HIV assembly and budding, as well as infection of new target cells, all depend on plasma membrane cholesterol. Depletion of cellular cholesterol markedly and reduces HIV-1 particle production [1,2], and cholesterolsequestering drugs, such as b-cyclodextrin, render the virus incompetent for cell entry [3,4]. Some clues to potential mechanisms that may be employed by HIV to achieve this goal have been provided recently when it was demonstrated that HIV-1 accessory protein Nef binds cholesterol and may deliver it to the site of virion assembly at the plasma membrane [5]. Little is known about the relation of this mechanism to major cellular cholesterol trafficking pathways and about the effect of HIV infection on lipid metabolism in the host cells
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