HIV infection and high density lipoprotein metabolism

Abstract

HIV infection and its treatment are associated with dyslipidemia, including hypoalphalipoproteinemia, and increased risk of cardiovascular disease. Parameters of HDL metabolism in HIV-positive patients were investigated in a cross-sectional study. The following groups of subjects were selected: (i) 25 treatment-naïve HIV-infected patients or HIV-infected patients on long therapy break, (ii) 28 HIV-infected patients currently treated with protease inhibitors, and (iii) 33 HIV-negative subjects. Compared to the HIV-negative group, all groups of HIV-infected patients were characterized by significantly elevated triglyceride and apolipoprotein B levels, mass and activity of lecithin cholesterol acyl transferase and cholesteryl ester transfer protein (p<0.01). Total and LDL cholesterol was lower in treatment-naïve HIV-infected group only. HDL cholesterol and prebeta(1)-HDL were significantly lower in all HIV-infected groups (p<0.05), while mean levels of apolipoprotein A-I (apoA-I) and ability of plasma to promote cholesterol efflux were similar in all groups. We found a positive correlation between apoA-I and levels of CD4+ cells (r(2)=0.3, p<0.001). Plasma level of phospholipid transfer protein was reduced in the group on antiretroviral therapy. Taken together these results suggest that HIV infection is associated with modified HDL metabolism re-directing cholesterol to the apoB-containing lipoproteins and likely reducing the functionality of reverse cholesterol transport.

Figure 1. Scatter diagram of plasma apoA-I levels (A) and correlation between CD4+ cell levels and plasma apoA-I levels (B)

Percent of CD4+ cells and apoA-I levels were measured in 25 HIV-infected currently untreated, 28 HIV-infected treated and 33, HIV-negative subjects as described in the Methods section. ○ – HIV-negative group; ■ - HIV-infected treatment-naïve; • – HIV-infected currently untreated group; ▲– HIV-infected treated group. r²=0.3, p<0.001.

Figure 2. Correlation between plasma level of HDL-C and triglyceride concentration (A) or CETP activity (B)

CETP activity and plasma HDL-C and TG concentration were measured as described in the Methods section. ○ – HIV-negative group; ■ - HIV-infected treatment-naïve; • – HIV-infected currently untreated group; ▲– HIV-infected treated group. Regression curves shown are for HIV-negative group (A) and HIV-infected (B) groups.

Figure 3. Schematic representation of HIV-induced changes in RCT

In HIV-negative subjects (top) cholesterol is removed from the cells mainly by the action of ABC transporters, with the formation of discoidal preβ-HDL particles. These particles can be acted upon by lecithin cholesterol acyl transferase (LCAT) to form spherical mature α-HDL. The subsequent remodelling of mature α-HDL includes i) selective uptake of HDL-derived cholesteryl esters by the liver SR-B1; ii) uptake of whole HDL particles by liver through LDL receptor-related protein or other receptors; iii) exchange of cholesteryl esters for triglyceride from apoB-containing lipoproteins by the action of cholesteryl ester transfer protein (CETP). In HIV-infected subjects (bottom) combination of hypertriglyceridemia and high activity of LCAT and CETP enhance maturation of HDL particles but re-directs the later steps of RCT toward delivering cholesterol to atherogenic VLDL and LDL. That would likely result in more cholesterol delivered to extrahepatic cells.