Background: Although antiretroviral therapy (ART) has resulted in a marked decrease in AIDS-related morbidity and mortality, the therapeutic benefit is often limited by side effects such as metabolic derangement, lipodystrophy, hyperlipidemia and cardiovascular diseases. The underlying mechanisms of these toxicities are not well understood. With a high prevalence of metabolic syndrome, we investigated the effect of ART on cholesterol biosynthesis.
Methods: A case-control study of ART-induced toxicity was conducted. Cases comprised HIV-infected individuals (N=16) on ART with viral loads averaging 20 copies/ml. Cases were matched to HIV-uninfected controls (N=16) by age, sex, and race/ethnicity. RNA was isolated from PBMCs after which qRT-PCR was performed. Wilcoxon Rank Test was used to evaluate significance (p<0.05). The cholesterol regulation genes that were studied include: sterol regulatory element-binding protein 2 (SREBP2, sensory control), HMG CoA reductase (HMGCR, de novo synthesis), low density lipoprotein receptor (LDLR, uptake) and ATP-binding cassette transporter member 1 (ABCA1, efflux), AMP-activated protein kinase A1 & B2 (AMPKA1 & AMPKB2, markers of cellular energy status) as well as NR1H3 (also known as LXRα- liver x receptor alpha, a precursor to ABCA1).
Results: The age of participants ranged from 33 to 66 years; 69% males and 31% females. The ethnicity comprised of 25% Non Hispanic whites, 6% Hispanic white and 69% African Americans. The ART regimen of the cohort was mostly tenofovir/emtricitabine (44%), tenofovir/emtricitabine/efavirenz (19%) and zidovudine/lamivudine (6%). ABCA1 and HMGCR were upregulated in cases compared to healthy controls (p<0.01 and p=0.01 respectively) (Fig. 1).
Conclusion: ART might cause intracellular accumulation of cholesterol leading to upregulation of efflux gene, ABCA1. Perturbation of cholesterol biosynthesis may be in the causal pathway of ART-associated metabolic syndrome.
E. Paintsil, None
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