Elsevier

Atherosclerosis

Volume 244, January 2016, Pages 22-28
Atherosclerosis

Lipid metabolism in patients infected with Nef-deficient HIV-1 strain

https://doi.org/10.1016/j.atherosclerosis.2015.10.103Get rights and content

Highlights

  • Patients infected with Nef-deficient strain of HIV(ΔNefHIV) have reduced prevalence of hypoalphalipoproteinema.

  • Several lipid classes in plasma lipidomic profile are different in patients infected with WT HIV and ΔNefHIV.

  • HIV induced changes in profile of lipid metabolism related microRNA are attenuated in ΔNefHIV patients.

  • Findings are consistent with Nef playing a significant role in lipid abnormalities in HIV patients.

Abstract

Background

HIV protein Nef plays a key role in impairing cholesterol metabolism in both HIV infected and bystander cells. The existence of a small cohort of patients infected with Nef-deficient strain of HIV presented a unique opportunity to test the effect of Nef on lipid metabolism in a clinical setting.

Methods

Here we report the results of a study comparing six patients infected with Nef-deficient strain of HIV (ΔNefHIV) with six treatment-naïve patients infected with wild-type HIV (WT HIV). Lipoprotein profile, size and functionality of high density lipoprotein (HDL) particles as well as lipidomic and microRNA profiles of patient plasma were analyzed.

Results

We found that patients infected with ΔNefHIV had lower proportion of subjects with plasma HDL-C levels <1 mmol/l compared to patients infected with WT HIV. Furthermore, compared to a reference group of HIV-negative subjects, there was higher abundance of smaller under-lipidated HDL particles in plasma of patients infected with WT HIV, but not in those infected with ΔNefHIV. Lipidomic analysis of plasma revealed differences in abundance of phosphatidylserine and sphingolipids between patients infected with ΔNefHIV and WT HIV. MicroRNA profiling revealed that plasma abundance of 24 miRNAs, many of those involved in regulation of lipid metabolism, was differentially regulated by WT HIV and ΔNefHIV.

Conclusion

Our findings are consistent with HIV protein Nef playing a significant role in pathogenesis of lipid-related metabolic complications of HIV disease.

Introduction

HIV disease is characterized by severe metabolic complications including dyslipidemia and atherosclerosis [1], [2]. Adverse side-effects of antiretroviral regimens were originally blamed for these complications, however, as development of better treatment regimens with reduced effect on lipid metabolism did not eliminate dyslipidemia [3] and high risk of atherosclerosis [4], it is becoming increasingly clear that HIV disease itself makes a substantial contribution to the pathogenesis of these complications. We have demonstrated that HIV protein Nef inhibits cholesterol efflux causing cholesterol accumulation in HIV-infected macrophages [5]. The same effect was observed in uninfected cells treated with recombinant Nef or with plasma containing soluble Nef released from infected cells [6]. Furthermore, recombinant Nef injected in mice in vivo caused atherosclerosis and dyslipidemia supporting a key role of Nef in pathogenesis of HIV-associated metabolic abnormalities [7]. However, no clinical evidence supporting the role of Nef in lipid dysregulation is available.

In this study we analyzed plasma samples of six patients infected with Nef-deficient strain of HIV-1 (ΔNefHIV), all members of the Sydney Blood Bank Cohort (SBBC). Pathogenicity and immunogenicity of this strain have been described in previous publications [8], [9], [10], [11] and summarized in a recent review [12]. In brief, all patients were infected with the same strain of HIV-1 through blood transfusion; they were slow-progressors or non-progressors and remained asymptomatic for an extended period of time [12]. Lipid metabolism in these patients was never investigated and, considering a potentially key role of Nef in the pathogenesis of HIV related impairment of lipid metabolism, these patients provided a unique opportunity to elucidate the role of Nef in HIV-associated metabolic disorders in a clinical setting.

Section snippets

Patients

Patients infected with Nef-deficient strain of HIV-1 (ΔNefHIV, n = 6) were all members of the SBBC cohort. Clinical and immunological parameters of these patients were originally described in several publications [8], [9], [10], [11]; age, sex, CD4+ cell count and viral load values for these patients are shown in Table 1 in comparison to the same parameters in WT HIV subjects. All patients, except patient D36, were not receiving antiretroviral therapy. Two subjects (C49, C64) were

Plasma lipoproteins

Patient plasma lipoprotein and apolipoprotein levels are shown in Table 1. Total cholesterol, triglyceride and apolipoprotein B levels were similar between the groups, while LDL-C levels trended higher in WT HIV group. In comparison to a reference group of HIV-negative subjects level of HDL-C was reduced by 25% in WT HIV infected patients, but only by 8% in ΔNefHIV infected subjects, however, due to limited power of the study these substantial differences did not reach statistical significance.

Discussion

Metabolic complications are an important part of HIV disease and include impairment of cellular and systemic lipid metabolism and enhanced development of atherosclerosis. We have demonstrated the key role of HIV protein Nef in disturbances of cellular cholesterol metabolism caused by HIV infection [5]. Nef is an HIV accessory protein expressed early in infection; it is located on the plasma membrane of infected cells (for review see [19]) and is also released from infected cells. The documented

Limitations

This study has several important limitations. First, the group size of ΔNefHIV infected patients was small. Unfortunately, the cohort of these patients is unique and no more patients infected with ΔNefHIV are known to us, therefore, this cohort could not be expanded. A change in the treatment guidelines shifting initiation of treatment to primary care also prevented expansion of the matching treatment-naïve WT HIV group. The ΔNefHIV group included two female patients, but both were of

Funding sources

This study was supported by grants from the National Health and Medical Research Council of Australia (GNT1019847) and NIH (HL101274) to DS and MB and in part by the Victorian Government's OIS Program. DS, PM and AH are Fellows of the National Health and Medical Research Council of Australia.

Conflict of interests

The authors have no conflict of interest to disclose.

References (27)

  • Z. Mujawar et al.

    Human immunodeficiency virus impairs reverse cholesterol transport from macrophages

    PLoS Biol.

    (2006)
  • B.F. Asztalos et al.

    Circulating Nef induces dyslipidemia in simian immunodeficiency virus-infected macaques by suppressing cholesterol efflux

    J. Infect. Dis.

    (2010)
  • H.L. Cui et al.

    HIV protein Nef causes dyslipidemia and formation of foam cells in mouse models of atherosclerosis

    FASEB J.

    (2014)
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    1

    Current address: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, 3086, Australia.

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