Human Immunodeficiency Virus Impairs Reverse Cholesterol Transport from Macrophages

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.

Dynamics of lung macrophage activation in response to helminth infection

“…1H). This ultrastructural appearance was similar to the macrophages identified in the lungs as a result of several infectious agents including HIV and tuberculosis [21,22]. Ultrastructural analysis of days 13-15 PI granular macro-phages (Fig.…”

HDL in Infectious Diseases and Sepsis

“…Of note, the HIV-1 Nef protein can impair ABCA1 cholesterol efflux from macrophages, thus supporting atherosclerosis. This viral inhibition of efflux was correlated with a direct interaction between ABCA1 and Nef Mujawar et al 2006). More recently it was shown that Nef downregulates ABCA1 function by a posttranslational mechanism that stimulates ABCA1 degradation but does not require the ability of Nef to bind ABCA1 .…”

Dynamin 2 is required for the enhancement of HIV-1 infectivity by Nef

“…It has been suggested that Nef enhances HIV-1 infectivity by increasing the cholesterol content of progeny virions, based on the observation that Nef impaired the efflux of cholesterol from macrophages by down-regulating the ATP-binding cassette transporter A1 (55). However, our results argue against the possibility that Dyn2 is required for a Nef-mediated increase in virion cholesterol, because Dyn2(K 44 A) did not counteract the effect of Nef but rather appeared to moderately increase virion cholesterol levels (SI Fig.…”