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.
Methods
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.
Results
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).
Conclusions
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.
References
1.
GiraltM., DomingoP., GuallarJ.P.HIV-1 infection alters gene expression in adipose tissue, which contributes to HIV-1/HAART-associated lipodystrophy. Antivir Ther2006; 11: 729–740.
2.
HammondE., NolanD., JamesI., MetcalfC., MallalS.Reduction of mitochondrial DNA content and respiratory chain activity occurs in adipocytes within 6-12 months of commencing nucleoside reverse transcriptase inhibitor therapy. AIDS2004; 18: 815–817.
3.
MiróO., LópezS., PedrolE.Mitochondrial DNA depletion and respiratory chain enzyme deficiencies are present in peripheral blood mononuclear cells of HIV-infected patients with HAART-related lipodystrophy. Antivir Ther2003; 8: 333–338.
4.
CarrA., SamarasK., BurtonS.A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS1998; 12: F51–F58.
5.
ShlayJ.C., SharmaS., PengG., GibertC.L., GrunfeldC.Long-term subcutaneous tissue changes among antiretroviral-naive persons initiating stavudine, zidovudine, or abacavir with lamivudine. J Acquir Immune Defic Syndr2008; 48: 53–62.
6.
ArribasJ.R., PozniakA.L., GallantJ.E.Tenofovir disoproxil fumarate, emtricitabine, and efavirenz compared with zidovudine/lamivudine and efavirenz in treatment-naive patients: 144-week analysis. J Acquir Immune Defic Syndr2008; 47: 74–78.
7.
BoothbyM., McGeeK.C., TomlinsonJ.W.Adipocyte differentiation, mitochondrial gene expression and fat distribution: differences between zidovudine and tenofovir after 6 months. Antivir Ther2009; 14: 1089–1100.
MallonP.W., MillerJ., CooperD.A., CarrA.Prospective evaluation of the effects of antiretroviral therapy on body composition in HIV-1-infected men starting therapy. AIDS2003; 17: 971–979.
10.
JacobsonD.L., TangA.M., SpiegelmanD.Incidence of metabolic syndrome in a cohort of HIV-infected adults and prevalence relative to the US population (National Health and Nutrition Examination Survey). J Acquir Immune Defic Syndr2006; 43: 458–466.
11.
WandH., CalmyA., CareyD.L.Metabolic syndrome, cardiovascular disease and type 2 diabetes mellitus after initiation of antiretroviral therapy in HIV infection. AIDS2007; 21: 2445–2453.
12.
MatthewsD.R., HoskerJ.P., RudenskiA.S., NaylorB.A., TreacherD.F., TurnerR.C.Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia1985; 28: 412–419.
13.
TomlinsonJ.W., WalkerE.A., BujalskaI.J.11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr Rev2004; 25: 831–866.
McComseyG.A., PaulsenD.M., LonerganJ.T.Improvements in lipoatrophy, mitochondrial DNA levels and fat apoptosis after replacing stavudine with abacavir or zidovudine. AIDS2005; 19: 15–23.
16.
SpiegelmanB.M., PuigserverP., WuZ.Regulation of adipogenesis and energy balance by PPARgamma and PGC-1. Int J Obes Relat Metab Disord2000; 24Suppl 4: S8–S10.
17.
ScarpullaR.C.Nuclear control of respiratory gene expression in mammalian cells. J Cell Biochem2006; 97: 673–683.
18.
CanninoG., Di LiegroC.M., RinaldiA.M.Nuclear-mitochondrial interaction. Mitochondrion2007; 7: 359–366.
19.
NolanD., MallalS.Antiretroviral-therapy-associated lipoatrophy: current status and future directions. Sex Health2005; 2: 153–163.
ChevillotteE., GiraltM., MirouxB., RicquierD., VillarroyaF.Uncoupling protein-2 controls adiponectin gene expression in adipose tissue through the modulation of reactive oxygen species production. Diabetes2007; 56: 1042–1050.
22.
LagathuC., EustaceB., ProtM.Some HIV antiretrovirals increase oxidative stress and alter chemokine, cytokine or adiponectin production in human adipocytes and macrophages. Antivir Ther2007; 12: 489–500.
23.
PaceC.S., MartinA.M., HammondE.L., MamotteC.D., NolanD.A., MallalS.A.Mitochondrial proliferation, DNA depletion and adipocyte differentiation in subcutaneous adipose tissue of HIV-positive HAART recipients. Antivir Ther2003; 8: 323–331.
24.
KannistoK., SutinenJ., KorsheninnikovaE.Expression of adipogenic transcription factors, peroxisome proliferator-activated receptor gamma co-activator 1, IL-6 and CD45 in subcutaneous adipose tissue in lipodystrophy associated with highly active antiretroviral therapy. AIDS2003; 17: 1753–1762.
25.
Medina-GomezG., GrayS., Vidal-PuigA.Adipogenesis and lipotoxicity: role of peroxisome proliferator-activated receptor gamma (PPARgamma) and PPARgamma coactivator-1 (PGC1). Public Health Nutr2007; 10: 1132–1137.
26.
CaronM., AuclairM., LagathuC.The HIV-1 nucleoside reverse transcriptase inhibitors stavudine and zidovudine alter adipocyte functions in vitro. AIDS2004; 18: 2127–2136.
27.
CarrA., WorkmanC., SmithD.E.Abacavir substitution for nucleoside analogs in patients with HIV lipoatrophy: a randomized trial. JAMA2002; 288: 207–215.
28.
MartinA., SmithD.E., CarrA.Reversibility of lipoatrophy in HIV-infected patients 2 years after switching from a thymidine analogue to abacavir: the MITOX Extension Study. AIDS2004; 18: 1029–1036.
29.
PozniakA.L., GallantJ.E., DeJesusE.Tenofovir disoproxil fumarate, emtricitabine, and efavirenz versus fixed-dose zidovudine/lamivudine and efavirenz in antiretroviral-naive patients: virologic, immunologic, and morphologic changes – a 96-week analysis. J Acquir Immune Defic Syndr2006; 43: 535–540.
30.
Pérez-MolinaJ.A., DomingoP., MartínezE., MorenoS.The role of efavirenz compared with protease inhibitors in the body fat changes associated with highly active antiretroviral therapy. J Antimicrob Chemother2008; 62: 234–245.
31.
De PauwA., TejerinaS., RaesM., KeijerJ., ArnouldT.Mitochondrial (dys)function in adipocyte (de) differentiation and systemic metabolic alterations. Am J Pathol2009; 175: 927–939.
32.
DubéM.P., KomarowL., MulliganK.Long-term body fat outcomes in antiretroviral-naive participants randomized to nelfinavir or efavirenz or both plus dual nucleosides. Dual X-ray absorptiometry results from A5005s, a substudy of Adult Clinical Trials Group 384. J Acquir Immune Defic Syndr2007; 45: 508–514.
33.
LafontanM., BerlanM.Do regional differences in adipocyte biology provide new pathophysiological insights?Trends Pharmacol Sci2003; 24: 276–283.
34.
DeveaudC., BeauvoitB., HagryS.Site specific alterations of adipose tissue mitochondria in 3′-azido-3′-deoxythymidine (AZT)-treated rats: an early stage in lipodystrophy?Biochem Pharmacol2005; 70: 90–101.
35.
KosmiskiL.A., BacchettiP., KotlerD.P.Relationship of fat distribution with adipokines in human immunodeficiency virus infection. J Clin Endocrinol Metab2008; 93: 216–224.
36.
CaronM., VigourouxC., BastardJ.P., CapeauJ.Adipocyte dysfunction in response to antiretroviral therapy: clinical, tissue and in-vitro studies. Curr Opin HIV AIDS2007; 2: 268–273.
37.
BrinkmanK., SmeitinkJ.A., RomijnJ.A., ReissP.Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet1999; 354: 1112–1115.
BastardJ.P., CaronM., VidalH.Association between altered expression of adipogenic factor SREBP1 in lipoatrophic adipose tissue from HIV-1-infected patients and abnormal adipocyte differentiation and insulin resistance. Lancet2002; 359: 1026–1031.
40.
GarciaA., VictorV.M., Gomez-SolerM., Gomes-SucerquiaL.J., ApostolovaN., EspluguesJ.V.EFV-induced reduction of mitochondrial respiration is due to inhibition of complex I. Antivir Ther2009; 14Suppl 2: A61.
41.
HaubrichR.H., RiddlerS.A., DiRienzoA.G.Metabolic outcomes in a randomized trial of nucleoside, nonnucleoside and protease inhibitor-sparing regimens for initial HIV treatment. AIDS2009; 23: 1109–1118.
42.
PulsR.L., SrasuebkulP., PetroumenosK., EmeryS., CooperD.A.Anthropometric and metabolic outcomes in a 48-week randomised, open-label study of three different combination antiretroviral regimens as initial therapy for HIV infection. Antivir Ther2009; 14Suppl 2: A8.
43.
MoyleG., GivensN., PearceH., CompstonJ.Effects of ART on bone turnover markers and bone density in HIV-infected patients. Antivir Ther2009; 14Suppl 2: A14.
44.
FleuryC., MignotteB., VayssièreJ.L.Mitochondrial reactive oxygen species in cell death signaling. Biochimie2002; 84: 131–141.
45.
MazatJ.P., RossignolR., MalgatM., RocherC., FaustinB., LetellierT.What do mitochondrial diseases teach us about normal mitochondrial functions…that we already knew: threshold expression of mitochondrial defects. Biochim Biophys Acta2001; 1504: 20–30.
46.
LenazG., BaraccaA., CarelliV., D'AurelioM., SgarbiG., SolainiG.Bioenergetics of mitochondrial diseases associated with mtDNA mutations. Biochim Biophys Acta2004; 1658: 89–94.
47.
El HadriK., GlorianM., MonsempesC.In vitro suppression of the lipogenic pathway by the nonnucleoside reverse transcriptase inhibitor efavirenz in 3T3 and human preadipocytes or adipocytes. J Biol Chem2004; 279: 15130–15141.
48.
Gallego-EscuredoJ.M., Del Mar GutierrezM., Diaz-DelfinJ.Differential effects of efavirenz and lopinavir/ritonavir on human adipocyte differentiation, gene expression and release of adipokines and pro-inflammatory cytokines. Curr HIV Res2010; 8: 545–553.
49.
CaronM., AuclairtM., VissianA., VigourouxC., CapeauJ.Contribution of mitochondrial dysfunction and oxidative stress to cellular premature senescence induced by antiretroviral thymidine analogues. Antivir Ther2008; 13: 27–38.
50.
CampisiJ., d'Adda di FagagnaF.Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol2007; 8: 729–740.
51.
CampisiJ., VijgJ.Does damage to DNA and other macromolecules play a role in aging? If so, how?J Gerontol A Biol Sci Med Sci2009; 64A: 175–178.
52.
BrownT.T., ColeS.R., LiX.Antiretroviral therapy and the prevalence and incidence of diabetes mellitus in the multicenter AIDS cohort study. Arch Intern Med2005; 165: 1179–1184.
53.
LawM.G., D'Armino MonforteA., Friis-MollerN.Cardio- and cerebrovascular events and predicted rates of myocardial infarction in the D:A:D Study.11th Conference on Retroviruses and Opportunistic Infections. 8–11 February 2004, San Fransisco, CA USA. Abstract 737.
54.
PhillipsA.N., NeatonJ., LundgrenJ.D.The role of HIV in serious diseases other than AIDS. AIDS2008; 22: 2409–2418.
55.
CurrierJ.S., BoydF., KawabataH., DeziiC., BurtcelB., HodderS.Diabetes mellitus and HIV infection.9th Conference on Retroviruses and Opportunistic Infected Individuals. 24–28 February 2002. Abstract 677-T.
