Impaired lipoprotein processing in HIV patients on antiretroviral therapy: aberrant high-density lipoprotein lipids, stability, and function

Abstract

Objective: HIV patients on antiretroviral therapy (HIV/ART) exhibit a unique atherogenic dyslipidemic profile with hypertriglyceridemia (HTG) and low plasma concentrations of high-density lipoprotein (HDL) cholesterol. In the Heart Positive Study of HIV/ART patients, a hypolipidemic therapy of fenofibrate, niacin, diet, and exercise reduced HTG and plasma non-HDL cholesterol concentrations and raised plasma HDL cholesterol and adiponectin concentrations. We tested the hypothesis that HIV/ART HDL have abnormal structures and properties and are dysfunctional.

Approach and results: Hypolipidemic therapy reduced the TG contents of low-density lipoprotein and HDL. At baseline, HIV/ART low-density lipoproteins were more triglyceride (TG)-rich and HDL were more TG- and cholesteryl ester-rich than the corresponding lipoproteins from normolipidemic (NL) subjects. Very-low-density lipoproteins, low-density lipoprotein, and HDL were larger than the corresponding lipoproteins from NL subjects; HIV/ART HDL were less stable than NL HDL. HDL-[(3)H]cholesteryl ester uptake by Huh7 hepatocytes was used to assess HDL functionality. HIV/ART plasma were found to contain significantly less competitive inhibition activity for hepatocyte HDL-cholesteryl ester uptake than NL plasma were found to contain (P<0.001).

Conclusions: Compared with NL subjects, lipoproteins from HIV/ART patients are larger and more neutral lipid-rich, and their HDL are less stable and less receptor-competent. On the basis of this work and previous studies of lipase activity in HIV, we present a model in which plasma lipolytic activities or hepatic cholesteryl ester uptake are impaired in HIV/ART patients. These findings provide a rationale to determine whether the distinctive lipoprotein structure, properties, and function of HIV/ART HDL predict atherosclerosis as assessed by carotid artery intimal medial thickness.

Trial registration: ClinicalTrials.gov NCT00246376.

Keywords: HIV dyslipidemia; hepatocyte cholesteryl ester uptake; high-density lipoprotein function; lipoprotein composition.

Figures

Figure 1

Comparison of the Effects of Four Different Anti Lipidemic Therapies vs. Placebo Control on LDL and HDL Composition. LDL and HDL %CE and % TG weight composition are shown as median, box plot of (25 – 75)% range and bar (10 – 90)% range at entry (white bars) and after therapy (gray bars). Therapy Groups 1 – 5 are denoted on the abscissa. Wilcoxon signed rank sum analysis of paired entry and after therapy values are indicated for pp=0.003 and 0.004, respectively.

Figure 2

Effects of Freezing on HDL as Assessed by SEC. Top Panel, A – D, Four different HIV/ART HDL samples after three freeze-thaw cycles. Bottom Panel, A – D, a single NL Control HDL sample analyzed before freezing and after one to three freeze-thaw cycles.

Figure 3

Comparison of the Stability of HDL from HIV/ART and NL Control Subjects. A, B: Examples of SEC profiles of NL and HIV/ART HDL before (gray shaded curve) and after (line) treatment with 2M GdmCl. Stability was assessed on the basis of the HDL peak height after treatment (C) and the ratio of lipid-free apo A-I/HDLfused ratio. Less fused (lipidated) HDL and more lipid-free apo A-I is formed from the HDL of the HIV/ART patients than from those of the the NL Control.

Figure 4

Comparison of Lipoprotein Sizes by SEC of TLP from NL Control and HIV/ART Subjects. Plots in A and B respectively are the average SEC profiles of the TLP from 12 NL Control and 10 HIV/ART Subjects. Individual chromatograms are in Supplemental Figure III. The insert in B is a 10X expansion of that region of the chromatogram to better reveal peaks for IDL and LDL. The black and grey lines represent the mean and standard error of the chromatograms. The dashed grey lines demonstrate that the average size of VLDL, LDL and HDL are larger in HIV/ART than in NL subjects.

Figure 5

Relative amounts of VLDL and IDL in HIV/ART and NL Control Plasma. Peak heights for each lipoprotein were determined from the individual donor TLP chromatograms shown in Supplemental Figure II. The ratios of VLDL and IDL relative to LDL are shown in A and B, and relative to HDL in C and D. HIV/ART plasma contains significantly more VLDL (p

Figure 6

Inhibition of Hepatocyte HDL CE Uptake by HDL from NL and HIV/ART Subjects. A, ID50% for individual donor HDL indicating inhibitory activity per mg HDL protein. B, Inhibitory potency of each patient's plasma expressed in terms of the volume of plasma needed to achieve 50% inhibition. Black dots: individual values; gray dot and bars: mean ± SE. The combination of low plasma HDL-C and the higher median ID50% in the HIV/ART versus NL Control subjects results in an average ID50% equivalent that is 41% lower for the HIV/ART vs NL subjects, p<0.001.

Figure 7

Metabolic model for the production of dysfunctional lipoproteins in HIV/ART dyslipidemia. See text for discussion.