HIV Infection and Antiretroviral Therapy Have Divergent Effects on Mitochondria in Adipose Tissue

Combination antiretroviral therapy (ART) has led to improvements in the morbidity and mortality associated with human immunodeficiency virus (HIV) infection, but chronic ART use can result in a variety of drug-related toxicities. Nucleoside reverse transcriptase inhibitors (NRTIs), which inhibit the RNA-dependent DNA polymerase activity of HIV reverse transcriptase, are nearly universally included in current ART regimens [1]. Unfortunately, NRTIs can inhibit mitochondrial DNA (mtDNA) polymerase γ, which is required for mtDNA replication, resulting in a reduction in mtDNA content per cell [2, 3] and potentially impairing mitochondrial function [4, 5]. First observed in muscle tissues of patients receiving zidovudine therapy [6], mtDNA depletion and consequent mitochondrial dysfunction have subsequently been postulated as mechanisms for other NRTI toxicity syndromes [4, 5, 7]. A low mtDNA/nuclear DNA (nDNA) ratio in PBMCs has been described with NRTI-associated symptomatic hyperlactemia [8, 9]. Mitochondrial DNA depletion has been demonstrated in subcutaneous adipose tissue of patients receiving NRTI-containing therapy, suggesting that NRTI-mediated mtDNA depletion plays a role in the pathogenesis of lipodystrophy [10–12]. Clinical studies have confirmed the association of specific NRTI agents with lipoatrophy [13, 14] and in vitro studies have shown that NRTIs such as zidovudine, stavudine, and didanosine result in mtDNA depletion [3]. Mitochondrial dysfunction is not consistently associated with mtDNA depletion [15, 16], and significant reductions in mtDNA have been described in asymptomatic subjects [17, 18]. Therefore, other mechanisms leading to mitochondrial dysfunction have been proposed as contributing to NRTI toxicity syndromes, including alterations in mitochondrial mass or gene expression, that do not rely on inhibition of DNA polymerase γ. NRTIs may decrease mtRNA transcription without an associated depletion of mtDNA [19]. HIV infection itself may cause mitochondrial toxicity [20, 21], although the mechanism has not been established. To better understand the effects of HIV and ART on mitochondrial number and function, we undertook a cross-sectional study to examine histopathology, mtDNA content, and the expression of mitochondrial-related genes in muscle, adipose tissue, and peripheral blood mononuclear cells (PBMCs) of HIV-infected adults and HIV-negative control subjects.