Plasma cholesterol efflux capacity from human THP-1 macrophages is reduced in HIV-infected patients: impact of HAART

Abstract

The capacity of HDL to remove cholesterol from macrophages is inversely associated with the severity of angiographic coronary artery disease. The effect of human immunodeficiency virus (HIV) infection or its treatment on the ability of HDL particles to stimulate cholesterol efflux from human macrophages has never been studied. We evaluated the capacity of whole plasma and isolated HDL particles from HIV-infected subjects (n = 231) and uninfected controls (n = 200), as well as in a subset of 41 HIV subjects receiving highly active antiretroviral therapy (HAART) to mediate cholesterol efflux from human macrophages. Plasma cholesterol efflux capacity was reduced (-12%; P = 0.001) in HIV patients as compared with controls. HIV infection reduced by 27% (P < 0.05) the capacity of HDL subfractions to promote cholesterol efflux from macrophages. We observed a reduced ABCA1-dependent efflux capacity of plasma (-27%; P < 0.0001) from HIV-infected subjects as a result of a reduction in the efflux capacity of HDL3 particles. HAART administration restored the capacity of plasma from HIV patients to stimulate cholesterol efflux from human macrophages (9.4%; P = 0.04). During HIV infection, the capacity of whole plasma to remove cholesterol from macrophages is reduced, thus potentially contributing to the increased coronary heart disease in the HIV population. HAART administration restored the removal of cholesterol from macrophages by increasing HDL functionality.

Keywords: antiretroviral therapy; high density lipoprotein function; highly active antiretroviral therapy; human immunodeficiency virus; macrophage cholesterol efflux; reverse cholesterol transport.

Copyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc.

Figures

Fig. 1.

Impact of HIV infection on plasma levels of lipoprotein subclasses isolated by gradient ultracentrifugation in HIV-infected subjects (n = 231; closed bars) and HIV-uninfected controls (n = 200; open bars) (A, B) and in a subset of HIV-infected patients before (n = 41; closed bars) and after HAART (n = 41; hatched bars) (C, D). A–C: Bar graphs showing levels of VLDL, IDL, and LDL subclasses. B–D: Bar graphs showing HDL subfraction levels. Values are mean ± SEM. *P < 0.05 versus controls; ‡P < 0.05 versus HIV-infected patients before treatment.

Fig. 2.

A–D: Bar graphs showing ABCA1-dependent efflux capacity of plasma (A, C), or isolated HDL subspecies (B, D) determined in HIV-infected subjects (n = 231; closed bars) and HIV-uninfected controls (n = 200; open bars) (A, B) and in a subset of HIV-infected patients before (n = 41; closed bars) and after HAART (n = 41; hatched bars) (C, D). The ABCA1-dependent efflux was calculated as the difference between fractional cholesterol efflux to cells in the presence or absence of tetracycline after 4 h incubation in the presence of 40-fold-diluted plasma or isolated HDL particles. E–H: Bar graphs showing SR-BI-dependent efflux capacity of plasma (E, G) or isolated HDL subspecies (F, H) determined in HIV-infected subjects (n = 231; closed bars) and controls (n = 200; open bars) (E, F) and in a subset of HIV-infected patients before (n = 41; closed bars) and after HAART (n = 41; hatched bars) (G, H). The SR-BI-dependent cholesterol efflux was determined in cultured rat hepatoma Fu5AH cells expressing high levels of SR-BI. The capacity of HDL2 (2b and 2a) and HDL3 (3a, 3b, and 3c) subfractions to mediate FC efflux through the ABCA1 (B, C) and SR-BI (F, H) pathways and expressed per moles of HDL particles. Values are mean ± SEM. *P < 0.05 versus controls; ‡P < 0.05 versus HIV-infected patients before treatment.

Fig. 3.

A: Bar graphs showing efflux capacity of total plasma apoAI- or apoB-containing lipoproteins determined in HIV-infected subjects (n = 231; closed bars) and HIV-uninfected controls (n = 200; open bars). B: Bar graphs showing efflux capacity of total plasma apoAI- or apoB-containing lipoproteins in a subset of HIV-infected subjects before (n = 41; closed bars) and after HAART (n = 41; hatched bars). The SR-BI-dependent cholesterol efflux toward total plasma apoAI-containing lipoproteins was determined using 40-fold-diluted apoB-depleted plasma. The SR-BI-dependent cholesterol efflux toward total plasma apoB-containing lipoproteins was calculated as the difference between fractional cholesterol efflux measured in the presence of 40-fold-diluted plasma from that measured in the presence of 40-fold-diluted apoB-depleted plasma. Values are mean ± SEM. *P < 0.0001 versus controls; ‡P < 0.006 versus HIV-infected patients before treatment.

Fig. 4.

Bar graphs showing efflux capacity from cholesterol loaded human THP-1 macrophages of plasma (A, C) and isolated HDL subspecies (B, D) determined in HIV-infected subjects (n = 231; closed bars) (A, B), in HIV-uninfected controls (n = 200; open bars), and in a subset of HIV-infected patients before (n = 41; closed bars) and after HAART (n = 41; hatched bars) (C, D). Values are mean ± SEM. *P < 0.05 versus controls; ‡P < 0.05 versus HIV-infected patients before treatment.

Fig. 5.

Integrated mechanism of the intracellular and extracellular consequences of HIV infection that control cholesterol homeostasis in human macrophages. HIV penetrates into macrophages through a direct interaction with CCR5 and CXCR4 receptors. It has been formerly demonstrated that HIV-specific protein Nef binds to ABCA1 and inhibits its efflux functions in human macrophages (31). Thus, by reducing cholesterol efflux through ABCA1 toward circulating lipid-poor/lipid-free apoAI and to small HDL3 subspecies, HIV infection potentially alters plasma cholesterol efflux capacity from human macrophages. In parallel, following HIV infection, major structural and functional modifications in plasma lipoproteins occur resulting in a reduction of the capacity of HDL particles to stimulate cholesterol efflux through the ABCA1 pathway. Taken together those effects of HIV infection on human macrophage homeostasis might significantly increase the risk of cardiovascular disease and favor the progression of atherosclerosis in HIV-infected patients. Increasing the capacity of plasma to stimulate cholesterol efflux via ABCA1, the major macrophage cholesterol transporter, is an interesting approach to reduce cardiovascular risk in this population. HAART restores HDL-mediated cholesterol efflux from macrophages either directly by acting on its metabolism or indirectly by suppressing viral charge and thus eliminating HIV adverse effects on HDL functionality.