Evidence for a Shift to Anaerobic Metabolism in Adipose Tissue in Efavirenz-Containing Regimens for HIV with Different Nucleoside Backbones

Abstract

Antiretroviral (ARV) treatment has been associated with abnormalities in lipid and mitochondrial metabolism. We compared patterns of gene expression in the subcutaneous adipose tissue (SAT) of HIV-positive subjects before and after 18-24 months of ARV therapy with HIV-negative controls. HIV patients naive to ARV were randomized to receive zidovudine (AZT), lamivudine (3TC) with efavirenz (EFV) or tenofovir disoproxil fumarate (TDF) with emtricitabine (FTC) and EFV. Healthy controls (n=15) were matched for age, ethnicity and gender. Patients on a regimen containing abacavir (ABC), 3TC and EFV for 18-24 months were also tested. Genes involved in adipocyte glucocorticoid, lipid and mitochondrial metabolism, and adipocyte differentiation, were profiled with real-time PCR. AZT led to increased visceral adipose tissue (VAT; P=0.012) and VAT:SAT ratio (P=0.036), whereas TDF increased SAT (P=0.047) and peripheral fat/lean body mass ratio (P=0.017). HIV treatment-naive patients had lower plasma lipoprotein lipase (LPL) activity (P=0.0001) versus controls (remaining below controls after ARV; P=0.038-0.0001). The overall pattern of gene expression was similar across all treatment groups, being most marked with AZT and least with TDF. There was up-regulation of peroxisome proliferator-activated receptor-γ coactivator-1α, uncoupling protein-2 and hexose 6-phosphate dehydrogenase, and down-regulation of nuclear respiratory factor-1, cytochrome oxidase B, cytochrome c oxidase-4, uncoupling protein-3, 11β-hydroxysteroid dehydrogenase type-1, glucocorticoid receptor-α, fatty acid synthase, fatty acid binding protein-4, LPL and hormone sensitive lipase (18-24 months post-treatment versus pretreatment levels and controls; P<0.05 to <0.0001). The decreased expression of genes involved in lipid and mitochondrial metabolism 18-24 months post-ARV treatment in SAT of HIV patients, in conjunction with the increase in uncoupling protein-2 and decrease in cytochrome oxidase B gene expression, provides evidence of mitochondrial dysfunction and a shift to anaerobic metabolism within SAT in EFV-containing ARV regimens.