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

Giralt M. , Domingo P. , Guallar J.P. HIV-1 infection alters gene expression in adipose tissue, which contributes to HIV-1/HAART-associated lipodystrophy. Antivir Ther 2006; 11: 729–740.

Hammond E. , Nolan D. , James I. , Metcalf C. , Mallal S. Reduction of mitochondrial DNA content and respiratory chain activity occurs in adipocytes within 6-12 months of commencing nucleoside reverse transcriptase inhibitor therapy. AIDS 2004; 18: 815–817.

Miró O. , López S. , Pedrol E. Mitochondrial DNA depletion and respiratory chain enzyme deficiencies are present in peripheral blood mononuclear cells of HIV-infected patients with HAART-related lipodystrophy. Antivir Ther 2003; 8: 333–338.

Carr A. , Samaras K. , Burton S. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS 1998; 12: F51–F58.

Shlay J.C. , Sharma S. , Peng G. , Gibert C.L. , Grunfeld C. Long-term subcutaneous tissue changes among antiretroviral-naive persons initiating stavudine, zidovudine, or abacavir with lamivudine. J Acquir Immune Defic Syndr 2008; 48: 53–62.

Arribas J.R. , Pozniak A.L. , Gallant J.E. Tenofovir disoproxil fumarate, emtricitabine, and efavirenz compared with zidovudine/lamivudine and efavirenz in treatment-naive patients: 144-week analysis. J Acquir Immune Defic Syndr 2008; 47: 74–78.

Boothby M. , McGee K.C. , Tomlinson J.W. Adipocyte differentiation, mitochondrial gene expression and fat distribution: differences between zidovudine and tenofovir after 6 months. Antivir Ther 2009; 14: 1089–1100.

Kratz M. , Purnell J.Q. , Breen P.A. Reduced adipogenic gene expression in thigh adipose tissue precedes human immunodeficiency virus-associated lipoatrophy. J Clin Endocrinol Metab 2008; 93: 959–966.

Mallon P.W. , Miller J. , Cooper D.A. , Carr A. Prospective evaluation of the effects of antiretroviral therapy on body composition in HIV-1-infected men starting therapy. AIDS 2003; 17: 971–979.

Jacobson D.L. , Tang A.M. , Spiegelman D. 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 Syndr 2006; 43: 458–466.

Wand H. , Calmy A. , Carey D.L. Metabolic syndrome, cardiovascular disease and type 2 diabetes mellitus after initiation of antiretroviral therapy in HIV infection. AIDS 2007; 21: 2445–2453.

Matthews D.R. , Hosker J.P. , Rudenski A.S. , Naylor B.A. , Treacher D.F. , Turner R.C. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412–419.

Tomlinson J.W. , Walker E.A. , Bujalska I.J. 11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr Rev 2004; 25: 831–866.

Lavery G.G. , Walker E.A. , Draper N. Hexose-6-phosphate dehydrogenase knock-out mice lack 11 beta-hydroxysteroid dehydrogenase type 1-mediated glucocorticoid generation. J Biol Chem 2006; 281: 6546–6551.

McComsey G.A. , Paulsen D.M. , Lonergan J.T. Improvements in lipoatrophy, mitochondrial DNA levels and fat apoptosis after replacing stavudine with abacavir or zidovudine. AIDS 2005; 19: 15–23.

Spiegelman B.M. , Puigserver P. , Wu Z. Regulation of adipogenesis and energy balance by PPARgamma and PGC-1. Int J Obes Relat Metab Disord 2000; 24 Suppl 4: S8–S10.

Scarpulla R.C. Nuclear control of respiratory gene expression in mammalian cells. J Cell Biochem 2006; 97: 673–683.

Cannino G. , Di Liegro C.M. , Rinaldi A.M. Nuclear-mitochondrial interaction. Mitochondrion 2007; 7: 359–366.

Nolan D. , Mallal S. Antiretroviral-therapy-associated lipoatrophy: current status and future directions. Sex Health 2005; 2: 153–163.

Rousset S. , Alves-Guerra M.C. , Mozo J. The biology of mitochondrial uncoupling proteins. Diabetes 2004; 53 Suppl 1: S130–S135.

Chevillotte E. , Giralt M. , Miroux B. , Ricquier D. , Villarroya F. Uncoupling protein-2 controls adiponectin gene expression in adipose tissue through the modulation of reactive oxygen species production. Diabetes 2007; 56: 1042–1050.

Lagathu C. , Eustace B. , Prot M. Some HIV antiretrovirals increase oxidative stress and alter chemokine, cytokine or adiponectin production in human adipocytes and macrophages. Antivir Ther 2007; 12: 489–500.

Pace C.S. , Martin A.M. , Hammond E.L. , Mamotte C.D. , Nolan D.A. , Mallal S.A. Mitochondrial proliferation, DNA depletion and adipocyte differentiation in subcutaneous adipose tissue of HIV-positive HAART recipients. Antivir Ther 2003; 8: 323–331.

Kannisto K. , Sutinen J. , Korsheninnikova E. 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. AIDS 2003; 17: 1753–1762.

Medina-Gomez G. , Gray S. , Vidal-Puig A. Adipogenesis and lipotoxicity: role of peroxisome proliferator-activated receptor gamma (PPARgamma) and PPARgamma coactivator-1 (PGC1). Public Health Nutr 2007; 10: 1132–1137.

Caron M. , Auclair M. , Lagathu C. The HIV-1 nucleoside reverse transcriptase inhibitors stavudine and zidovudine alter adipocyte functions in vitro. AIDS 2004; 18: 2127–2136.

Carr A. , Workman C. , Smith D.E. Abacavir substitution for nucleoside analogs in patients with HIV lipoatrophy: a randomized trial. JAMA 2002; 288: 207–215.

Martin A. , Smith D.E. , Carr A. Reversibility of lipoatrophy in HIV-infected patients 2 years after switching from a thymidine analogue to abacavir: the MITOX Extension Study. AIDS 2004; 18: 1029–1036.

Pozniak A.L. , Gallant J.E. , DeJesus E. 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 Syndr 2006; 43: 535–540.

Pérez-Molina J.A. , Domingo P. , Martínez E. , Moreno S. The role of efavirenz compared with protease inhibitors in the body fat changes associated with highly active antiretroviral therapy. J Antimicrob Chemother 2008; 62: 234–245.

De Pauw A. , Tejerina S. , Raes M. , Keijer J. , Arnould T. Mitochondrial (dys)function in adipocyte (de) differentiation and systemic metabolic alterations. Am J Pathol 2009; 175: 927–939.

Dubé M.P. , Komarow L. , Mulligan K. 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 Syndr 2007; 45: 508–514.

Lafontan M. , Berlan M. Do regional differences in adipocyte biology provide new pathophysiological insights? Trends Pharmacol Sci 2003; 24: 276–283.

Deveaud C. , Beauvoit B. , Hagry S. Site specific alterations of adipose tissue mitochondria in 3′-azido-3′-deoxythymidine (AZT)-treated rats: an early stage in lipodystrophy? Biochem Pharmacol 2005; 70: 90–101.

Kosmiski L.A. , Bacchetti P. , Kotler D.P. Relationship of fat distribution with adipokines in human immunodeficiency virus infection. J Clin Endocrinol Metab 2008; 93: 216–224.

Caron M. , Vigouroux C. , Bastard J.P. , Capeau J. Adipocyte dysfunction in response to antiretroviral therapy: clinical, tissue and in-vitro studies. Curr Opin HIV AIDS 2007; 2: 268–273.

Brinkman K. , Smeitink J.A. , Romijn J.A. , Reiss P. Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet 1999; 354: 1112–1115.

Zaera M.G. , Miró O. , Pedrol E. Mitochondrial involvement in antiretroviral therapy-related lipodystrophy. AIDS 2001; 15: 1643–1651.

Bastard J.P. , Caron M. , Vidal H. Association between altered expression of adipogenic factor SREBP1 in lipoatrophic adipose tissue from HIV-1-infected patients and abnormal adipocyte differentiation and insulin resistance. Lancet 2002; 359: 1026–1031.

Garcia A. , Victor V.M. , Gomez-Soler M. , Gomes-Sucerquia L.J. , Apostolova N. , Esplugues J.V. EFV-induced reduction of mitochondrial respiration is due to inhibition of complex I. Antivir Ther 2009; 14 Suppl 2: A61.

Haubrich R.H. , Riddler S.A. , DiRienzo A.G. Metabolic outcomes in a randomized trial of nucleoside, nonnucleoside and protease inhibitor-sparing regimens for initial HIV treatment. AIDS 2009; 23: 1109–1118.

Puls R.L. , Srasuebkul P. , Petroumenos K. , Emery S. , Cooper D.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 Ther 2009; 14 Suppl 2: A8.

Moyle G. , Givens N. , Pearce H. , Compston J. Effects of ART on bone turnover markers and bone density in HIV-infected patients. Antivir Ther 2009; 14 Suppl 2: A14.

Fleury C. , Mignotte B. , Vayssière J.L. Mitochondrial reactive oxygen species in cell death signaling. Biochimie 2002; 84: 131–141.

Mazat J.P. , Rossignol R. , Malgat M. , Rocher C. , Faustin B. , Letellier T. What do mitochondrial diseases teach us about normal mitochondrial functions…that we already knew: threshold expression of mitochondrial defects. Biochim Biophys Acta 2001; 1504: 20–30.

Lenaz G. , Baracca A. , Carelli V. , D'Aurelio M. , Sgarbi G. , Solaini G. Bioenergetics of mitochondrial diseases associated with mtDNA mutations. Biochim Biophys Acta 2004; 1658: 89–94.

El Hadri K. , Glorian M. , Monsempes C. In vitro suppression of the lipogenic pathway by the nonnucleoside reverse transcriptase inhibitor efavirenz in 3T3 and human preadipocytes or adipocytes. J Biol Chem 2004; 279: 15130–15141.

Gallego-Escuredo J.M. , Del Mar Gutierrez M. , Diaz-Delfin J. Differential effects of efavirenz and lopinavir/ritonavir on human adipocyte differentiation, gene expression and release of adipokines and pro-inflammatory cytokines. Curr HIV Res 2010; 8: 545–553.

Caron M. , Auclairt M. , Vissian A. , Vigouroux C. , Capeau J. Contribution of mitochondrial dysfunction and oxidative stress to cellular premature senescence induced by antiretroviral thymidine analogues. Antivir Ther 2008; 13: 27–38.

Campisi J. , d'Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 2007; 8: 729–740.

Campisi J. , Vijg J. Does damage to DNA and other macromolecules play a role in aging? If so, how? J Gerontol A Biol Sci Med Sci 2009; 64A: 175–178.

Brown T.T. , Cole S.R. , Li X. Antiretroviral therapy and the prevalence and incidence of diabetes mellitus in the multicenter AIDS cohort study. Arch Intern Med 2005; 165: 1179–1184.

Law M.G. , D'Armino Monforte A. , Friis-Moller N. 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.

Phillips A.N. , Neaton J. , Lundgren J.D. The role of HIV in serious diseases other than AIDS. AIDS 2008; 22: 2409–2418.

Currier J.S. , Boyd F. , Kawabata H. , Dezii C. , Burtcel B. , Hodder S. Diabetes mellitus and HIV infection. 9th Conference on Retroviruses and Opportunistic Infected Individuals. 24–28 February 2002. Abstract 677-T.

Currier J.S. , Taylor A. , Boyd F. Coronary heart disease in HIV-infected individuals. J Acquir Immune Defic Syndr 2003; 33: 506–512.

Dolan S.E. , Hadigan C. , Killilea K.M. Increased cardiovascular disease risk indices in HIV-infected women. J Acquir Immune Defic Syndr 2005; 39: 44–54.