Differential adipose tissue gene expression profiles in abacavir treated patients that may contribute to the understanding of cardiovascular risk: a microarray study.

Jeremy W Tomlinson,Meg Boothby,Mohsen Shahmanesh,Kenneth Phillips

doi:10.1371/journal.pone.0117164

Abstract

ObjectiveTo compare changes in gene expression by microarray from subcutaneous adipose tissue from HIV treatment naïve patients treated with efavirenz based regimens containing abacavir (ABC), tenofovir (TDF) or zidovidine (AZT).DesignSubcutaneous fat biopsies were obtained before, at 6- and 18–24-months after treatment, and from HIV negative controls. Groups were age, ethnicity, weight, biochemical profile, and pre-treatment CD4 count matched. Microarray data was generated using the Agilent Whole Human Genome Microarray. Identification of differentially expressed genes and genomic response pathways was performed using limma and gene set enrichment analysis.ResultsThere were significant divergences between ABC and the other two groups 6 months after treatment in genes controlling cell adhesion and environmental information processing, with some convergence at 18–24 months. Compared to controls the ABC group, but not AZT or TDF showed enrichment of genes controlling adherence junction, at 6 months and 18–24 months (adjusted p<0.05) and focal adhesions and tight junction at 6 months (p<0.5). Genes controlling leukocyte transendothelial migration (p<0.05) and ECM-receptor interactions (p = 0.04) were over-expressed in ABC compared to TDF and AZT at 6 months but not at 18–24 months. Enrichment of pathways and individual genes controlling cell adhesion and environmental information processing were specifically dysregulated in the ABC group in comparison with other treatments. There was little difference between AZT and TDF.ConclusionAfter initiating treatment, there is divergence in the expression of genes controlling cell adhesion and environmental information processing between ABC and both TDF and AZT in subcutaneous adipose tissue. If similar changes are also taking place in other tissues including the coronary vasculature they may contribute to the increased risk of cardiovascular events reported in patients recently started on abacavir-containing regimens.

Highlights

Antiviral therapies for HIV infection have been associated with abnormalities in serum lipids, [1] an increased incidence of type 2 diabetes mellitus,[2] and increased cardiovascular disease. [3,4,5,6,7] the metabolic and adipose tissue effects of antiretroviral regimens are not the same with all regimens.[8]
If similar changes are taking place in other tissues including the coronary vasculature they may contribute to the increased risk of cardiovascular events reported in patients recently started on abacavir-containing regimens
We have previously reported changes in the expression of genes controlling lipid metabolism and mitochondrial respiratory chain in biopsies taken from patients 6 and 18–24 months after starting antiretroviral regimens containing different nucleoside analogue regimens combined with efavirenz. [19,20] Here we report results from a microarray study performed on subcutaneous adipose tissue biopsies from the same study

Summary

Introduction

Antiviral therapies for HIV infection have been associated with abnormalities in serum lipids, [1] an increased incidence of type 2 diabetes mellitus,[2] and increased cardiovascular disease. [3,4,5,6,7] the metabolic and adipose tissue effects of antiretroviral regimens are not the same with all regimens.[8]. Antiviral therapies for HIV infection have been associated with abnormalities in serum lipids, [1] an increased incidence of type 2 diabetes mellitus,[2] and increased cardiovascular disease. [3,4,5,6,7] the metabolic and adipose tissue effects of antiretroviral regimens are not the same with all regimens.[8] Regimens containing tenofovir disoproxil fumarate (TDF) have demonstrated less effect on serum lipids and subcutaneous adipose tissue than those containing zidovidine (AZT).[9] treatment with abacavir-containing regimens has been associated with increased risk of cardiovascular disease in some studies [10,11,12,13,14] but not others [15,16,17,18].

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Results

Conclusion