Comprehensive Physiology Wiley Online Library

Adipose Tissue in HIV Infection

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ABSTRACT

HIV infection and antiretroviral therapy (ART) treatment exert diverse effects on adipocytes and stromal‐vascular fraction cells, leading to changes in adipose tissue quantity, distribution, and energy storage. A HIV‐associated lipodystrophic condition was recognized early in the epidemic, characterized by clinically apparent changes in subcutaneous, visceral, and dorsocervical adipose depots. Underlying these changes is altered adipose tissue morphology and expression of genes central to adipocyte maturation, regulation, metabolism, and cytokine signaling. HIV viral proteins persist in circulation and locally within adipose tissue despite suppression of plasma viremia on ART, and exposure to these proteins impairs preadipocyte maturation and reduces adipocyte expression of peroxisome proliferator‐activated receptor gamma (PPAR‐γ) and other genes involved in cell regulation. Several early nucleoside reverse transcriptase inhibitor and protease inhibitor antiretroviral drugs demonstrated substantial adipocyte toxicity, including reduced mitochondrial DNA content and respiratory chain enzymes, reduced PPAR‐γ and other regulatory gene expression, and increased proinflammatory cytokine production. Newer‐generation agents, such as integrase inhibitors, appear to have fewer adverse effects. HIV infection also alters the balance of CD4+ and CD8+ T cells in adipose tissue, with effects on macrophage activation and local inflammation, while the presence of latently infected CD4+ T cells in adipose tissue may constitute a protected viral reservoir. This review provides a synthesis of the literature on how HIV virus, ART treatment, and host characteristics interact to affect adipose tissue distribution, immunology, and contribution to metabolic health, and adipocyte maturation, cellular regulation, and energy storage. © 2017 American Physiological Society. Compr Physiol 7:1339‐1357, 2017.

References
 1. Abraham L , Fackler OT . HIV‐1 Nef: A multifaceted modulator of T cell receptor signaling. Cell Commun Signal 10: 39, 2012.
 2. Agarwal N , Iyer D , Patel SG , Sekhar RV , Phillips TM , Schubert U , Oplt T , Buras ED , Samson SL , Couturier J , Lewis DE , Rodriguez‐Barradas MC , Jahoor F , Kino T , Kopp JB , Balasubramanyam A . HIV‐1 Vpr induces adipose dysfunction in vivo through reciprocal effects on PPAR/GR co‐regulation. Sci Transl Med 5: 213ra164, 2013.
 3. Ambrosino C , Ruocco MR , Chen X , Mallardo M , Baudi F , Trematerra S , Quinto I , Venuta S , Scala G . HIV‐1 Tat induces the expression of the interleukin‐6 (IL6) gene by binding to the IL6 leader RNA and by interacting with CAAT enhancer‐binding protein beta (NF‐IL6) transcription factors. J Biol Chem 272: 14883‐14892, 1997.
 4. Apostolova N , Blas‐Garcia A , Esplugues JV . Mitochondrial interference by anti‐HIV drugs: Mechanisms beyond Pol‐gamma inhibition. Trends Pharmacol Sci 32: 715‐725, 2011.
 5. Apostolova N , Blas‐Garcia A , Esplugues JV . Mitochondrial toxicity in HAART: An overview of in vitro evidence. Curr Pharm Des 17: 2130‐2144, 2011.
 6. Bacchetti P , Gripshover B , Grunfeld C , Heymsfield S , McCreath H , Osmond D , Saag M , Scherzer R , Shlipak M , Tien P . Fat distribution in men with HIV infection. J Acquir Immune Defic Syndr 40: 121‐131, 2005.
 7. Balasubramanyam A , Mersmann H , Jahoor F , Phillips TM , Sekhar RV , Schubert U , Brar B , Iyer D , Smith EO , Takahashi H , Lu H , Anderson P , Kino T , Henklein P , Kopp JB . Effects of transgenic expression of HIV‐1 Vpr on lipid and energy metabolism in mice. Am J Physiol Endocrinol Metab 292: E40‐E48, 2007.
 8. Banga R , Procopio F , Cavassini M , Perreau M . In vitro reactivation of replication competent and infectious HIV‐1 by HDAC inhibitors. J Virol 90: 1858‐1871, 2015.
 9. Barre‐Sinoussi F , Chermann JC , Rey F , Nugeyre MT , Chamaret S , Gruest J , Dauguet C , Axler‐Blin C , Vezinet‐Brun F , Rouzioux C , Rozenbaum W , Montagnier L . Isolation of a T‐lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 220: 868‐871, 1983.
 10. Barreiro P , Soriano V , Blanco F , Casimiro C , de la Cruz JJ , Gonzalez‐Lahoz J . Risks and benefits of replacing protease inhibitors by nevirapine in HIV‐infected subjects under long‐term successful triple combination therapy. AIDS 14: 807‐812, 2000.
 11. Bastard JP , Caron M , Vidal H , Jan V , Auclair M , Vigouroux C , Luboinski J , Laville M , Maachi M , Girard PM , Rozenbaum W , Levan P , Capeau J . 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 359: 1026‐1031, 2002.
 12. Batista ML, Jr. , Peres SB , McDonald ME , Alcantara PS , Olivan M , Otoch JP , Farmer SR , Seelaender M . Adipose tissue inflammation and cancer cachexia: Possible role of nuclear transcription factors. Cytokine 57: 9‐16, 2012.
 13. Ben‐Romano R , Rudich A , Tirosh A , Potashnik R , Sasaoka T , Riesenberg K , Schlaeffer F , Bashan N . Nelfinavir‐induced insulin resistance is associated with impaired plasma membrane recruitment of the PI 3‐kinase effectors Akt/PKB and PKC‐zeta. Diabetologia 47: 1107‐1117, 2004.
 14. Ben‐Romano R , Rudich A , Torok D , Vanounou S , Riesenberg K , Schlaeffer F , Klip A , Bashan N . Agent and cell‐type specificity in the induction of insulin resistance by HIV protease inhibitors. AIDS 17: 23‐32, 2003.
 15. Bennasser Y , Bahraoui E . HIV‐1 Tat protein induces interleukin‐10 in human peripheral blood monocytes: Involvement of protein kinase C‐betaII and ‐delta. FASEB J 16: 546‐554, 2002.
 16. Bereziat V , Cervera P , Le Dour C , Verpont MC , Dumont S , Vantyghem MC , Capeau J , Vigouroux C , Lipodystrophy Study G . LMNA mutations induce a non‐inflammatory fibrosis and a brown fat‐like dystrophy of enlarged cervical adipose tissue. Am J Pathol 179: 2443‐2453, 2011.
 17. Bernasconi E , Boubaker K , Junghans C , Flepp M , Furrer HJ , Haensel A , Hirschel B , Boggian K , Chave JP , Opravil M , Weber R , Rickenbach M , Telenti A , Swiss HIVCS . Abnormalities of body fat distribution in HIV‐infected persons treated with antiretroviral drugs: The Swiss HIV Cohort Study. J Acquir Immune Defic Syndr 31: 50‐55, 2002.
 18. Bogacka I , Xie H , Bray GA , Smith SR . Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo. Diabetes 54: 1392‐1399, 2005.
 19. Bonnet E , Delpierre C , Sommet A , Marion‐Latard F , Herve R , Aquilina C , Labau E , Obadia M , Marchou B , Massip P , Perret B , Bernard J . Total body composition by DXA of 241 HIV‐negative men and 162 HIV‐infected men: Proposal of reference values for defining lipodystrophy. J Clin Densitom 8: 287‐292, 2005.
 20. Brenchley JM , Paiardini M , Knox KS , Asher AI , Cervasi B , Asher TE , Scheinberg P , Price DA , Hage CA , Kholi LM , Khoruts A , Frank I , Else J , Schacker T , Silvestri G , Douek DC . Differential Th17 CD4 T‐cell depletion in pathogenic and nonpathogenic lentiviral infections. Blood 112: 2826‐2835, 2008.
 21. Brinkman K , Smeitink JA , Romijn JA , Reiss P . Mitochondrial toxicity induced by nucleoside‐analogue reverse‐transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral‐therapy‐related lipodystrophy. Lancet 354: 1112‐1115, 1999.
 22. Bruun JM , Lihn AS , Pedersen SB , Richelsen B . Monocyte chemoattractant protein‐1 release is higher in visceral than subcutaneous human adipose tissue (AT): implication of macrophages resident in the AT. J Clin Endocrinol Metab 90: 2282‐2289, 2005.
 23. Caron‐Debarle M , Lagathu C , Boccara F , Vigouroux C , Capeau J . HIV‐associated lipodystrophy: From fat injury to premature aging. Trends Mol Med 16: 218‐229, 2010.
 24. Caron M , Auclair M , Lagathu C , Lombes A , Walker UA , Kornprobst M , Capeau J . The HIV‐1 nucleoside reverse transcriptase inhibitors stavudine and zidovudine alter adipocyte functions in vitro. AIDS 18: 2127‐2136, 2004.
 25. Caron M , Auclair M , Sterlingot H , Kornprobst M , Capeau J . Some HIV protease inhibitors alter lamin A/C maturation and stability, SREBP‐1 nuclear localization and adipocyte differentiation. AIDS 17: 2437‐2444, 2003.
 26. Caron M , Auclair M , Vigouroux C , Glorian M , Forest C , Capeau J . The HIV protease inhibitor indinavir impairs sterol regulatory element‐binding protein‐1 intranuclear localization, inhibits preadipocyte differentiation, and induces insulin resistance. Diabetes 50: 1378‐1388, 2001.
 27. 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 13: 27‐38, 2008.
 28. Caron M , Vigouroux C , Bastard JP , Capeau J . Antiretroviral‐related adipocyte dysfunction and lipodystrophy in HIV‐infected patients: Alteration of the PPARgamma‐dependent pathways. PPAR Res 2009: 507141, 2009.
 29. Carr A , Samaras K , Burton S , Law M , Freund J , Chisholm DJ , Cooper DA . A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS 12: F51‐58, 1998.
 30. Carr A , Workman C , Smith DE , Hoy J , Hudson J , Doong N , Martin A , Amin J , Freund J , Law M , Cooper DA , Mitochondrial Toxicity Study G. Abacavir substitution for nucleoside analogs in patients with HIV lipoatrophy: A randomized trial. JAMA 288: 207‐215, 2002.
 31. Carter VM , Hoy JF , Bailey M , Colman PG , Nyulasi I , Mijch AM . The prevalence of lipodystrophy in an ambulant HIV‐infected population: It all depends on the definition. HIV Med 2: 174‐180, 2001.
 32. Casteilla L , Cousin B , Carmona M . PPARs and Adipose Cell Plasticity. PPAR Res 2007: 68202, 2007.
 33. Centers for Disease Control and Prevention. HIV Surveillance Report, 2013 Available at: http://www.cdc.gov/hiv/library/reports/surveillance/. Published February 2015.
 34. Centers for Disease Control and Prevention. Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. Council of State and Territorial Epidemiologists; AIDS Program, Center for Infectious Diseases. MMWR Morb Mortal Wkly Rep 36(Suppl 1): 1S‐15S, 1987.
 35. Cereijo R , Gallego‐Escuredo JM , Moure R , Villarroya J , Domingo JC , Fontdevila J , Martinez E , Gutierrez Mdel M , Mateo MG , Giralt M , Domingo P , Villarroya F . The molecular signature of HIV‐1‐associated lipomatosis reveals differential involvement of brown and Beige/Brite adipocyte cell lineages. PLoS One 10: e0136571, 2015.
 36. Chang HC , Samaniego F , Nair BC , Buonaguro L , Ensoli B . HIV‐1 Tat protein exits from cells via a leaderless secretory pathway and binds to extracellular matrix‐associated heparan sulfate proteoglycans through its basic region. AIDS 11: 1421‐1431, 1997.
 37. Chen CH , Cheng YC . Delayed cytotoxicity and selective loss of mitochondrial DNA in cells treated with the anti‐human immunodeficiency virus compound 2′,3′‐dideoxycytidine. J Biol Chem 264: 11934‐11937, 1989.
 38. Chen CH , Vazquez‐Padua M , Cheng YC . Effect of anti‐human immunodeficiency virus nucleoside analogs on mitochondrial DNA and its implication for delayed toxicity. Mol Pharmacol 39: 625‐628, 1991.
 39. Chen P , Mayne M , Power C , Nath A . The Tat protein of HIV‐1 induces tumor necrosis factor‐alpha production. Implications for HIV‐1‐associated neurological diseases. J Biol Chem 272: 22385‐22388, 1997.
 40. Cherry CL , Gahan ME , McArthur JC , Lewin SR , Hoy JF , Wesselingh SL . Exposure to dideoxynucleosides is reflected in lowered mitochondrial DNA in subcutaneous fat. J Acquir Immune Defic Syndr 30: 271‐277, 2002.
 41. Cohen CJ , Andrade‐Villanueva J , Clotet B , Fourie J , Johnson MA , Ruxrungtham K , Wu H , Zorrilla C , Crauwels H , Rimsky LT , Vanveggel S , Boven K , and group Ts. Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment‐naive adults infected with HIV‐1 (THRIVE): A phase 3, randomised, non‐inferiority trial. Lancet 378: 229‐237, 2011.
 42. Cote HC. Possible ways nucleoside analogues can affect mitochondrial DNA content and gene expression during HIV therapy. Antivir Ther 10 (Suppl 2): M3‐11, 2005.
 43. Couturier J , Agarwal N , Nehete PN , Baze WB , Barry MA , Jagannadha Sastry K , Balasubramanyam A , Lewis DE . Infectious SIV resides in adipose tissue and induces metabolic defects in chronically infected rhesus macaques. Retrovirology 13: 30, 2016.
 44. Couturier J , Suliburk JW , Brown JM , Luke DJ , Agarwal N , Yu X , Nguyen C , Iyer D , Kozinetz CA , Overbeek PA , Metzker ML , Balasubramanyam A , Lewis DE . Human adipose tissue as a reservoir for memory CD4+ T cells and HIV. AIDS 29: 667‐674, 2015.
 45. Crane HM , Grunfeld C , Harrington RD , Uldall KK , Ciechanowski PS , Kitahata MM . Lipoatrophy among HIV‐infected patients is associated with higher levels of depression than lipohypertrophy. HIV Med 9: 780‐786, 2008.
 46. Creaven M , Hans F , Mutskov V , Col E , Caron C , Dimitrov S , Khochbin S . Control of the histone‐acetyltransferase activity of Tip60 by the HIV‐1 transactivator protein, Tat. Biochemistry 38: 8826‐8830, 1999.
 47. Damouche A , Lazure T , Avettand‐Fenoel V , Huot N , Dejucq‐Rainsford N , Satie AP , Melard A , David L , Gommet C , Ghosn J , Noel N , Pourcher G , Martinez V , Benoist S , Bereziat V , Cosma A , Favier B , Vaslin B , Rouzioux C , Capeau J , Muller‐Trutwin M , Dereuddre‐Bosquet N , Le Grand R , Lambotte O , Bourgeois C . Adipose tissue is a neglected viral reservoir and an inflammatory site during chronic HIV and SIV infection. PLoS Pathog 11: e1005153, 2015.
 48. De Barros S , Zakaroff‐Girard A , Lafontan M , Galitzky J , Bourlier V . Inhibition of human preadipocyte proteasomal activity by HIV protease inhibitors or specific inhibitor lactacystin leads to a defect in adipogenesis, which involves matrix metalloproteinase‐9. J Pharmacol Exp Ther 320: 291‐299, 2007.
 49. De Luca A , Nasi M , Di Giambenedetto S , Cozzi‐Lepri A , Pinti M , Marzocchetti A , Mussini C , Fabbiani M , Bracciale L , Cauda R , Cossarizza A . Mitochondrial DNA haplogroups and incidence of lipodystrophy in HIV‐infected patients on long‐term antiretroviral therapy. J Acquir Immune Defic Syndr 59: 113‐120, 2012.
 50. de Souza Dantas Oliveira SH , de Souza Aarao TL , da Silva Barbosa L , Souza Lisboa PG , Tavares Dutra CD , Margalho Sousa L , Simoes Quaresma JA , Feio Libonati RM . Immunohistochemical analysis of the expression of TNF‐alpha, TGF‐beta, and caspase‐3 in subcutaneous tissue of patients with HIV lipodystrophy syndrome. Microb Pathog 67‐68: 41‐47, 2014.
 51. Degris E , Delpierre C , Sommet A , Sire S , Lassoued S , Aquilina C , Marchou B , Massip P , Obadia M , Marion‐Latard F , Bonnet E , Bernard J . Longitudinal study of body composition of 101 HIV men with lipodystrophy: Dual‐energy X‐ray criteria for lipodystrophy evolution. J Clin Densitom 13: 237‐244, 2010.
 52. Deiuliis J , Shah Z , Shah N , Needleman B , Mikami D , Narula V , Perry K , Hazey J , Kampfrath T , Kollengode M , Sun Q , Satoskar AR , Lumeng C , Moffatt‐Bruce S , Rajagopalan S . Visceral adipose inflammation in obesity is associated with critical alterations in tregulatory cell numbers. PLoS One 6: e16376, 2011.
 53. Delpierre C , Bonnet E , Marion‐Latard F , Aquilina C , Obadia M , Marchou B , Massip P , Perret B , Bernard J . Impact of HIV infection on total body composition in treatment‐naive men evaluated by dual‐energy X‐ray absorptiometry comparison of 90 untreated HIV‐infected men to 241 controls. J Clin Densitom 10: 376‐380, 2007.
 54. Diaz‐Delfin J , del Mar Gutierrez M , Gallego‐Escuredo JM , Domingo JC , Gracia Mateo M , Villarroya F , Domingo P , Giralt M . Effects of nevirapine and efavirenz on human adipocyte differentiation, gene expression, and release of adipokines and cytokines. Antiviral Res 91: 112‐119, 2011.
 55. Diaz‐Delfin J , Domingo P , Giralt M , Villarroya F . Maraviroc reduces cytokine expression and secretion in human adipose cells without altering adipogenic differentiation. Cytokine 61: 808‐815, 2013.
 56. Diaz‐Delfin J , Domingo P , Mateo MG , Gutierrez Mdel M , Domingo JC , Giralt M , Villarroya F . Effects of rilpivirine on human adipocyte differentiation, gene expression, and release of adipokines and cytokines. Antimicrob Agents Chemother 56: 3369‐3375, 2012.
 57. Diaz‐Delfin J , Domingo P , Wabitsch M , Giralt M , Villarroya F . HIV‐1 Tat protein impairs adipogenesis and induces the expression and secretion of proinflammatory cytokines in human SGBS adipocytes. Antivir Ther 17: 529‐540, 2012.
 58. Domingo P , Gutierrez Mdel M , Gallego‐Escuredo JM , Torres F , Mateo MG , Villarroya J , Lamarca K , Domingo JC , Vidal F , Villarroya F , Giralt M . A 48‐week study of fat molecular alterations in HIV naive patients starting tenofovir/emtricitabine with lopinavir/ritonavir or efavirenz. J Acquir Immune Defic Syndr 66: 457‐465, 2014.
 59. Domingo P , Matias‐Guiu X , Pujol RM , Francia E , Lagarda E , Sambeat MA , Vazquez G . Subcutaneous adipocyte apoptosis in HIV‐1 protease inhibitor‐associated lipodystrophy. AIDS 13: 2261‐2267, 1999.
 60. Dorr P , Westby M , Dobbs S , Griffin P , Irvine B , Macartney M , Mori J , Rickett G , Smith‐Burchnell C , Napier C , Webster R , Armour D , Price D , Stammen B , Wood A , Perros M . Maraviroc (UK‐427,857), a potent, orally bioavailable, and selective small‐molecule inhibitor of chemokine receptor CCR5 with broad‐spectrum anti‐human immunodeficiency virus type 1 activity. Antimicrob Agents Chemother 49: 4721‐4732, 2005.
 61. Dowell P , Flexner C , Kwiterovich PO , Lane MD . Suppression of preadipocyte differentiation and promotion of adipocyte death by HIV protease inhibitors. J Biol Chem 275: 41325‐41332, 2000.
 62. Duffaut C , Zakaroff‐Girard A , Bourlier V , Decaunes P , Maumus M , Chiotasso P , Sengenes C , Lafontan M , Galitzky J , Bouloumie A . Interplay between human adipocytes and T lymphocytes in obesity: CCL20 as an adipochemokine and T lymphocytes as lipogenic modulators. Arterioscler Thromb Vasc Biol 29: 1608‐1614, 2009.
 63. El Hadri K , Glorian M , Monsempes C , Dieudonne MN , Pecquery R , Giudicelli Y , Andreani M , Dugail I , Feve B . In vitro suppression of the lipogenic pathway by the nonnucleoside reverse transcriptase inhibitor efavirenz in 3T3 and human preadipocytes or adipocytes. J Biol Chem 279: 15130‐15141, 2004.
 64. Ellery PJ , Tippett E , Chiu YL , Paukovics G , Cameron PU , Solomon A , Lewin SR , Gorry PR , Jaworowski A , Greene WC , Sonza S , Crowe SM . The CD16+ monocyte subset is more permissive to infection and preferentially harbors HIV‐1 in vivo. J Immunol 178: 6581‐6589, 2007.
 65. Engin F , Hotamisligil GS . Restoring endoplasmic reticulum function by chemical chaperones: An emerging therapeutic approach for metabolic diseases. Diabetes Obes Metab 12(Suppl 2): 108‐115, 2010.
 66. Ensoli B , Buonaguro L , Barillari G , Fiorelli V , Gendelman R , Morgan RA , Wingfield P , Gallo RC . Release, uptake, and effects of extracellular human immunodeficiency virus type 1 Tat protein on cell growth and viral transactivation. J Virol 67: 277‐287, 1993.
 67. Erlandson KM , Lake JE . Fat matters: Understanding the role of adipose tissue in health in HIV infection. Curr HIV/AIDS Rep 13: 20‐30, 2016.
 68. Esser R , Glienke W , von Briesen H , Rubsamen‐Waigmann H , Andreesen R . Differential regulation of proinflammatory and hematopoietic cytokines in human macrophages after infection with human immunodeficiency virus. Blood 88: 3474‐3481, 1996.
 69. Fabbrini E , Cella M , McCartney SA , Fuchs A , Abumrad NA , Pietka TA , Chen Z , Finck BN , Han DH , Magkos F , Conte C , Bradley D , Fraterrigo G , Eagon JC , Patterson BW , Colonna M , Klein S . Association between specific adipose tissue CD4+ T‐cell populations and insulin resistance in obese individuals. Gastroenterology 145: 366‐374 e361‐363, 2013.
 70. Feeney ER , Mallon PW . Impact of mitochondrial toxicity of HIV‐1 antiretroviral drugs on lipodystrophy and metabolic dysregulation. Curr Pharm Des 16: 3339‐3351, 2010.
 71. Feuerer M , Herrero L , Cipolletta D , Naaz A , Wong J , Nayer A , Lee J , Goldfine AB , Benoist C , Shoelson S , Mathis D . Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 15: 930‐939, 2009.
 72. Fong PS , Flynn DM , Evans CD , Korthuis PT . Integrase strand transfer inhibitor‐associated diabetes mellitus: A case report. Int J STD AIDS 28: 626‐628, 2016.
 73. Freitas P , Santos AC , Carvalho D , Pereira J , Marques R , Martinez E , Sarmento A , Medina JL . Fat mass ratio: An objective tool to define lipodystrophy in hiv‐infected patients under antiretroviral therapy. J Clin Densitom 13: 197‐203, 2010.
 74. Fu S , Watkins SM , Hotamisligil GS . The role of endoplasmic reticulum in hepatic lipid homeostasis and stress signaling. Cell Metab 15: 623‐634, 2012.
 75. Fyffe SA , Alphey MS , Buetow L , Smith TK , Ferguson MA , Sorensen MD , Bjorkling F , Hunter WN . Recombinant human PPAR‐beta/delta ligand‐binding domain is locked in an activated conformation by endogenous fatty acids. J Mol Biol 356: 1005‐1013, 2006.
 76. Gallego‐Escuredo JM , Del Mar Gutierrez M , Diaz‐Delfin J , Domingo JC , Mateo MG , Domingo P , Giralt M , Villarroya F . Differential effects of efavirenz and lopinavir/ritonavir on human adipocyte differentiation, gene expression and release of adipokines and pro‐inflammatory cytokines. Curr HIV Res 8: 545‐553, 2010.
 77. Gallego‐Escuredo JM , Villarroya J , Domingo P , Targarona EM , Alegre M , Domingo JC , Villarroya F , Giralt M . Differentially altered molecular signature of visceral adipose tissue in HIV‐1‐associated lipodystrophy. J Acquir Immune Defic Syndr 64: 142‐148, 2013.
 78. Galli M , Veglia F , Angarano G , Santambrogio S , Meneghini E , Gritti F , Cargnel A , Mazzotta F , Lazzarin A . Gender differences in antiretroviral drug‐related adipose tissue alterations. Women are at higher risk than men and develop particular lipodystrophy patterns. J Acquir Immune Defic Syndr 34: 58‐61, 2003.
 79. Galluzzi L , Pinti M , Troiano L , Prada N , Nasi M , Ferraresi R , Salomoni P , Mussini C , Cossarizza A . Changes in mitochondrial RNA production in cells treated with nucleoside analogues. Antivir Ther 10: 191‐195, 2005.
 80. Gao CL , Zhu C , Zhao YP , Chen XH , Ji CB , Zhang CM , Zhu JG , Xia ZK , Tong ML , Guo XR . Mitochondrial dysfunction is induced by high levels of glucose and free fatty acids in 3T3‐L1 adipocytes. Mol Cell Endocrinol 320: 25‐33, 2010.
 81. Gao D , Madi M , Ding C , Fok M , Steele T , Ford C , Hunter L , Bing C . Interleukin‐1beta mediates macrophage‐induced impairment of insulin signaling in human primary adipocytes. Am J Physiol Endocrinol Metab 307: E289‐304, 2014.
 82. Garrabou G , Lopez S , Moren C , Martinez E , Fontdevila J , Cardellach F , Gatell JM , Miro O . Mitochondrial damage in adipose tissue of untreated HIV‐infected patients. AIDS 25: 165‐170, 2011.
 83. Giralt M , Domingo P , Guallar JP , Rodriguez de la Concepcion ML , Alegre M , Domingo JC , Villarroya F . HIV‐1 infection alters gene expression in adipose tissue, which contributes to HIV‐1/HAART‐associated lipodystrophy. Antivir Ther 11: 729‐740, 2006.
 84. Giralt M , Domingo P , Villarroya F . Adipose tissue biology and HIV‐infection. Best Pract Res Clin Endocrinol Metab 25: 487‐499, 2011.
 85. Goebel F , Yakovlev A , Pozniak AL , Vinogradova E , Boogaerts G , Hoetelmans R , de Bethune MP , Peeters M , Woodfall B . Short‐term antiviral activity of TMC278–‐a novel NNRTI–‐in treatment‐naive HIV‐1‐infected subjects. AIDS 20: 1721‐1726, 2006.
 86. Gorjao R , Cury‐Boaventura MF , de Lima TM , Curi R . Regulation of human lymphocyte proliferation by fatty acids. Cell Biochem Funct 25: 305‐315, 2007.
 87. Grinspoon S , Corcoran C , Miller K , Biller BM , Askari H , Wang E , Hubbard J , Anderson EJ , Basgoz N , Heller HM , Klibanski A . Body composition and endocrine function in women with acquired immunodeficiency syndrome wasting. J Clin Endocrinol Metab 82: 1332‐1337, 1997.
 88. Grinspoon S , Corcoran C , Rosenthal D , Stanley T , Parlman K , Costello M , Treat M , Davis S , Burrows B , Basgoz N , Klibanski A . Quantitative assessment of cross‐sectional muscle area, functional status, and muscle strength in men with the acquired immunodeficiency syndrome wasting syndrome. J Clin Endocrinol Metab 84: 201‐206, 1999.
 89. Grunfeld C , Pang M , Shimizu L , Shigenaga JK , Jensen P , Feingold KR . Resting energy expenditure, caloric intake, and short‐term weight change in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. Am J Clin Nutr 55: 455‐460, 1992.
 90. Grunfeld C , Rimland D , Gibert CL , Powderly WG , Sidney S , Shlipak MG , Bacchetti P , Scherzer R , Haffner S , Heymsfield SB . Association of upper trunk and visceral adipose tissue volume with insulin resistance in control and HIV‐infected subjects in the FRAM study. J Acquir Immune Defic Syndr 46: 283‐290, 2007.
 91. Grunfeld C , Saag M , Cofrancesco J, Jr. , Lewis CE , Kronmal R , Heymsfield S , Tien PC , Bacchetti P , Shlipak M , Scherzer R . Regional adipose tissue measured by MRI over 5 years in HIV‐infected and control participants indicates persistence of HIV‐associated lipoatrophy. AIDS 24: 1717‐1726, 2010.
 92. Guallar JP , Gallego‐Escuredo JM , Domingo JC , Alegre M , Fontdevila J , Martinez E , Hammond EL , Domingo P , Giralt M , Villarroya F . Differential gene expression indicates that ‘buffalo hump’ is a distinct adipose tissue disturbance in HIV‐1‐associated lipodystrophy. AIDS 22: 575‐584, 2008.
 93. Hadigan C , Borgonha S , Rabe J , Young V , Grinspoon S . Increased rates of lipolysis among human immunodeficiency virus‐infected men receiving highly active antiretroviral therapy. Metabolism 51: 1143‐1147, 2002.
 94. Hadigan C , Kamin D , Liebau J , Mazza S , Barrow S , Torriani M , Rubin R , Weise S , Fischman A , Grinspoon S . Depot‐specific regulation of glucose uptake and insulin sensitivity in HIV‐lipodystrophy. Am J Physiol Endocrinol Metab 290: E289‐298, 2006.
 95. 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 18: 815‐817, 2004.
 96. Hasse B , Iff M , Ledergerber B , Calmy A , Schmid P , Hauser C , Cavassini M , Bernasconi E , Marzolini C , Tarr PE , Swiss HIVCS , Aubert V , Barth J , Battegay M , Boni J , Bucher HC , Burton‐Jeangros C , Egger M , Elzi L , Fehr J , Fellay J , Furrer H , Fux CA , Gorgievski M , Gunthard H , Haerry D , Hirsch HH , Hosli I , Kahlert C , Kaiser L , Keiser O , Klimkait T , Kouyos R , Kovari H , Martinetti G , Martinez de Tejada B , Metzner K , Muller N , Nadal D , Pantaleo G , Rauch A , Regenass S , Rickenbach M , Rudin C , Schoni‐Affolter F , Schultze D , Schupbach J , Speck R , Staehelin C , Tarr P , Telenti A , Trkola A , Vernazza P , Weber R , Yerly S . Obesity trends and body mass index changes after starting antiretroviral treatment: The Swiss HIV Cohort Study. Open Forum Infect Dis 1: ofu040, 2014.
 97. Haubrich RH , Riddler SA , DiRienzo AG , Komarow L , Powderly WG , Klingman K , Garren KW , Butcher DL , Rooney JF , Haas DW , Mellors JW , Havlir DV , Team ACTGAS. Metabolic outcomes in a randomized trial of nucleoside, nonnucleoside and protease inhibitor‐sparing regimens for initial HIV treatment. AIDS 23: 1109‐1118, 2009.
 98. Hazan U , Romero IA , Cancello R , Valente S , Perrin V , Mariot V , Dumonceaux J , Gerhardt CC , Strosberg AD , Couraud PO , Pietri‐Rouxel F . Human adipose cells express CD4, CXCR4, and CCR5 [corrected] receptors: A new target cell type for the immunodeficiency virus‐1? FASEB J 16: 1254‐1256, 2002.
 99. He J , Choe S , Walker R , Di Marzio P , Morgan DO , Landau NR . Human immunodeficiency virus type 1 viral protein R (Vpr) arrests cells in the G2 phase of the cell cycle by inhibiting p34cdc2 activity. J Virol 69: 6705‐6711, 1995.
 100. Heinzinger NK , Bukrinsky MI , Haggerty SA , Ragland AM , Kewalramani V , Lee MA , Gendelman HE , Ratner L , Stevenson M , Emerman M . The Vpr protein of human immunodeficiency virus type 1 influences nuclear localization of viral nucleic acids in nondividing host cells. Proc Natl Acad Sci U S A 91: 7311‐7315, 1994.
 101. Hellerstein MK , Grunfeld C , Wu K , Christiansen M , Kaempfer S , Kletke C , Shackleton CH . Increased de novo hepatic lipogenesis in human immunodeficiency virus infection. J Clin Endocrinol Metab 76: 559‐565, 1993.
 102. Henklein P , Bruns K , Sherman MP , Tessmer U , Licha K , Kopp J , de Noronha CM , Greene WC , Wray V , Schubert U . Functional and structural characterization of synthetic HIV‐1 Vpr that transduces cells, localizes to the nucleus, and induces G2 cell cycle arrest. J Biol Chem 275: 32016‐32026, 2000.
 103. Holness MJ , Sugden MC . Regulation of pyruvate dehydrogenase complex activity by reversible phosphorylation. Biochem Soc Trans 31: 1143‐1151, 2003.
 104. Hommes MJ , Romijn JA , Endert E , Sauerwein HP . Resting energy expenditure and substrate oxidation in human immunodeficiency virus (HIV)‐infected asymptomatic men: HIV affects host metabolism in the early asymptomatic stage. Am J Clin Nutr 54: 311‐315, 1991.
 105. Hotamisligil GS , Erbay E . Nutrient sensing and inflammation in metabolic diseases. Nat Rev Immunol 8: 923‐934, 2008.
 106. Hotamisligil GS , Peraldi P , Budavari A , Ellis R , White MF , Spiegelman BM . IRS‐1‐mediated inhibition of insulin receptor tyrosine kinase activity in TNF‐alpha‐ and obesity‐induced insulin resistance. Science 271: 665‐668, 1996.
 107. Howard LC , Liu CY , Purdy JB , Walter P , Bluemke DA , Hadigan C . Lipolytic rate associated with intramyocardial lipid in an HIV cohort without increased lipolysis. J Clin Endocrinol Metab 101: 151‐156, 2016.
 108. Hulgan T , Haubrich R , Riddler SA , Tebas P , Ritchie MD , McComsey GA , Haas DW , Canter JA . European mitochondrial DNA haplogroups and metabolic changes during antiretroviral therapy in AIDS Clinical Trials Group Study A5142. AIDS 25: 37‐47, 2011.
 109. Ioan‐Facsinay A , Kwekkeboom JC , Westhoff S , Giera M , Rombouts Y , van Harmelen V , Huizinga TW , Deelder A , Kloppenburg M , Toes RE . Adipocyte‐derived lipids modulate CD4+ T‐cell function. Eur J Immunol 43: 1578‐1587, 2013.
 110. Jacotot E , Ferri KF , El Hamel C , Brenner C , Druillennec S , Hoebeke J , Rustin P , Metivier D , Lenoir C , Geuskens M , Vieira HL , Loeffler M , Belzacq AS , Briand JP , Zamzami N , Edelman L , Xie ZH , Reed JC , Roques BP , Kroemer G . Control of mitochondrial membrane permeabilization by adenine nucleotide translocator interacting with HIV‐1 viral protein rR and Bcl‐2. J Exp Med 193: 509‐519, 2001.
 111. Jalbert E , Crawford TQ , D'Antoni ML , Keating SM , Norris PJ , Nakamoto BK , Seto T , Parikh NI , Shikuma CM , Ndhlovu LC , Barbour JD . IL‐1Beta enriched monocytes mount massive IL‐6 responses to common inflammatory triggers among chronically HIV‐1 infected adults on stable anti‐retroviral therapy at risk for cardiovascular disease. PLoS One 8: e75500, 2013.
 112. Jan V , Cervera P , Maachi M , Baudrimont M , Kim M , Vidal H , Girard PM , Levan P , Rozenbaum W , Lombes A , Capeau J , Bastard JP . Altered fat differentiation and adipocytokine expression are inter‐related and linked to morphological changes and insulin resistance in HIV‐1‐infected lipodystrophic patients. Antivir Ther 9: 555‐564, 2004.
 113. Jaworowski A , Kamwendo DD , Ellery P , Sonza S , Mwapasa V , Tadesse E , Molyneux ME , Rogerson SJ , Meshnick SR , Crowe SM . CD16+ monocyte subset preferentially harbors HIV‐1 and is expanded in pregnant Malawian women with Plasmodium falciparum malaria and HIV‐1 infection. J Infect Dis 196: 38‐42, 2007.
 114. Jernas M , Palming J , Sjoholm K , Jennische E , Svensson PA , Gabrielsson BG , Levin M , Sjogren A , Rudemo M , Lystig TC , Carlsson B , Carlsson LM , Lonn M . Separation of human adipocytes by size: Hypertrophic fat cells display distinct gene expression. FASEB J 20: 1540‐1542, 2006.
 115. Johnson JA , Albu JB , Engelson ES , Fried SK , Inada Y , Ionescu G , Kotler DP . Increased systemic and adipose tissue cytokines in patients with HIV‐associated lipodystrophy. Am J Physiol Endocrinol Metab 286: E261‐E271, 2004.
 116. Jones SP , Janneh O , Back DJ , Pirmohamed M . Altered adipokine response in murine 3T3‐F442A adipocytes treated with protease inhibitors and nucleoside reverse transcriptase inhibitors. Antivir Ther 10: 207‐213, 2005.
 117. Jones SP , Qazi N , Morelese J , Lebrecht D , Sutinen J , Yki‐Jarvinen H , Back DJ , Pirmohamed M , Gazzard BG , Walker UA , Moyle GJ . Assessment of adipokine expression and mitochondrial toxicity in HIV patients with lipoatrophy on stavudine‐ and zidovudine‐containing regimens. J Acquir Immune Defic Syndr 40: 565‐572, 2005.
 118. Jones SP , Waitt C , Sutton R , Back DJ , Pirmohamed M . Effect of atazanavir and ritonavir on the differentiation and adipokine secretion of human subcutaneous and omental preadipocytes. AIDS 22: 1293‐1298, 2008.
 119. Jowett JB , Planelles V , Poon B , Shah NP , Chen ML , Chen IS . The human immunodeficiency virus type 1 vpr gene arrests infected T cells in the G2 + M phase of the cell cycle. J Virol 69: 6304‐6313, 1995.
 120. Ju SM , Song HY , Lee JA , Lee SJ , Choi SY , Park J . Extracellular HIV‐1 Tat up‐regulates expression of matrix metalloproteinase‐9 via a MAPK‐NF‐kappaB dependent pathway in human astrocytes. Exp Mol Med 41: 86‐93, 2009.
 121. Juffermans NP , Verbon A , van Deventer SJ , van Deutekom H , Speelman P , van der Poll T . Tumor necrosis factor and interleukin‐1 inhibitors as markers of disease activity of tuberculosis. Am J Respir Crit Care Med 157: 1328‐1331, 1998.
 122. Kannisto K , Sutinen J , Korsheninnikova E , Fisher RM , Ehrenborg E , Gertow K , Virkamaki A , Nyman T , Vidal H , Hamsten A , Yki‐Jarvinen H . 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 17: 1753‐1762, 2003.
 123. Kedzierska K , Azzam R , Ellery P , Mak J , Jaworowski A , Crowe SM . Defective phagocytosis by human monocyte/macrophages following HIV‐1 infection: Underlying mechanisms and modulation by adjunctive cytokine therapy. J Clin Virol 26: 247‐263, 2003.
 124. Kim DJ , Westfall AO , Chamot E , Willig AL , Mugavero MJ , Ritchie C , Burkholder GA , Crane HM , Raper JL , Saag MS , Willig JH . Multimorbidity patterns in HIV‐infected patients: The role of obesity in chronic disease clustering. J Acquir Immune Defic Syndr 61: 600‐605, 2012.
 125. Kim MJ , Leclercq P , Lanoy E , Cervera P , Antuna‐Puente B , Maachi M , Dorofeev E , Slama L , Valantin MA , Costagliola D , Lombes A , Bastard JP , Capeau J . A 6‐month interruption of antiretroviral therapy improves adipose tissue function in HIV‐infected patients: The ANRS EP29 Lipostop Study. Antivir Ther 12: 1273‐1283, 2007.
 126. Kim RJ , Wilson CG , Wabitsch M , Lazar MA , Steppan CM . HIV protease inhibitor‐specific alterations in human adipocyte differentiation and metabolism. Obesity (Silver Spring) 14: 994‐1002, 2006.
 127. Kino T , Gragerov A , Kopp JB , Stauber RH , Pavlakis GN , Chrousos GP . The HIV‐1 virion‐associated protein vpr is a coactivator of the human glucocorticoid receptor. J Exp Med 189: 51‐62, 1999.
 128. Kintscher U , Hartge M , Hess K , Foryst‐Ludwig A , Clemenz M , Wabitsch M , Fischer‐Posovszky P , Barth TF , Dragun D , Skurk T , Hauner H , Bluher M , Unger T , Wolf AM , Knippschild U , Hombach V , Marx N . T‐lymphocyte infiltration in visceral adipose tissue: A primary event in adipose tissue inflammation and the development of obesity‐mediated insulin resistance. Arterioscler Thromb Vasc Biol 28: 1304‐1310, 2008.
 129. Kintscher U , Law RE . PPARgamma‐mediated insulin sensitization: The importance of fat versus muscle. Am J Physiol Endocrinol Metab 288: E287‐291, 2005.
 130. Koethe JR , Heimburger DC . Nutritional aspects of HIV‐associated wasting in sub‐Saharan Africa. Am J Clin Nutr 91: 1138S‐1142S, 2010.
 131. Koethe JR , Hulgan T , Niswender K . Adipose tissue and immune function: A review of evidence relevant to HIV infection. J Infect Dis 208: 1194‐1201, 2013.
 132. Koethe JR , Jenkins CA , Lau B , Shepherd BE , Justice AC , Tate JP , Buchacz K , Napravnik S , Mayor AM , Horberg MA , Blashill AJ , Willig A , Wester CW , Silverberg MJ , Gill J , Thorne JE , Klein M , Eron JJ , Kitahata MM , Sterling TR , Moore RD , North American ACCoR, and Design. Rising obesity prevalence and weight gain among adults starting antiretroviral therapy in the United States and Canada. AIDS Res Hum Retroviruses 32: 50‐58, 2016.
 133. Koh EH , Park JY , Park HS , Jeon MJ , Ryu JW , Kim M , Kim SY , Kim MS , Kim SW , Park IS , Youn JH , Lee KU . Essential role of mitochondrial function in adiponectin synthesis in adipocytes. Diabetes 56: 2973‐2981, 2007.
 134. Kosmiski L , Kuritzkes D , Hamilton J , Sharp T , Lichtenstien K , Hill J , Eckel R . Fat distribution is altered in HIV‐infected men without clinical evidence of the HIV lipodystrophy syndrome. HIV Med 4: 235‐240, 2003.
 135. Kotler DP , Tierney AR , Wang J , Pierson RN, Jr . Magnitude of body‐cell‐mass depletion and the timing of death from wasting in AIDS. Am J Clin Nutr 50: 444‐447, 1989.
 136. Kudlow BA , Jameson SA , Kennedy BK . HIV protease inhibitors block adipocyte differentiation independently of lamin A/C. AIDS 19: 1565‐1573, 2005.
 137. Ladha JS , Tripathy MK , Mitra D . Mitochondrial complex I activity is impaired during HIV‐1‐induced T‐cell apoptosis. Cell Death Differ 12: 1417‐1428, 2005.
 138. Lagathu C , Bastard JP , Auclair M , Maachi M , Kornprobst M , Capeau J , Caron M . Antiretroviral drugs with adverse effects on adipocyte lipid metabolism and survival alter the expression and secretion of proinflammatory cytokines and adiponectin in vitro. Antivir Ther 9: 911‐920, 2004.
 139. Lagathu C , Eustace B , Prot M , Frantz D , Gu Y , Bastard JP , Maachi M , Azoulay S , Briggs M , Caron M , Capeau J . Some HIV antiretrovirals increase oxidative stress and alter chemokine, cytokine or adiponectin production in human adipocytes and macrophages. Antivir Ther 12: 489‐500, 2007.
 140. Laspia MF , Rice AP , Mathews MB . HIV‐1 Tat protein increases transcriptional initiation and stabilizes elongation. Cell 59: 283‐292, 1989.
 141. Lawler HM , Underkofler CM , Kern PA , Erickson C , Bredbeck B , Rasouli N . Adipose tissue hypoxia, inflammation and fibrosis in obese insulin sensitive and obese insulin resistant subjects. J Clin Endocrinol Metab 101: 1422‐1428, 2016.
 142. Lee YH , Nair S , Rousseau E , Allison DB , Page GP , Tataranni PA , Bogardus C , Permana PA . Microarray profiling of isolated abdominal subcutaneous adipocytes from obese vs non‐obese Pima Indians: Increased expression of inflammation‐related genes. Diabetologia 48: 1776‐1783, 2005.
 143. Leroyer S , Vatier C , Kadiri S , Quette J , Chapron C , Capeau J , Antoine B . Glyceroneogenesis is inhibited through HIV protease inhibitor‐induced inflammation in human subcutaneous but not visceral adipose tissue. J Lipid Res 52: 207‐220, 2011.
 144. Lewis W , Day BJ , Copeland WC . Mitochondrial toxicity of NRTI antiviral drugs: An integrated cellular perspective. Nat Rev Drug Discov 2: 812‐822, 2003.
 145. Lihn AS , Richelsen B , Pedersen SB , Haugaard SB , Rathje GS , Madsbad S , Andersen O . Increased expression of TNF‐alpha, IL‐6, and IL‐8 in HALS: Implications for reduced adiponectin expression and plasma levels. Am J Physiol Endocrinol Metab 285: E1072‐1080, 2003.
 146. Liou YH , Wang SW , Chang CL , Huang PL , Hou MS , Lai YG , Lee GA , Jiang ST , Tsai CY , Liao NS . Adipocyte IL‐15 regulates local and systemic NK cell development. J Immunol 193: 1747‐1758, 2014.
 147. Lombardi R , Sambatakou H , Mariolis I , Cokkinos D , Papatheodoridis GV , Tsochatzis EA . Prevalence and predictors of liver steatosis and fibrosis in unselected patients with HIV mono‐infection. Dig Liver Dis 48: 1471‐1477, 2016.
 148. Lumeng CN , Bodzin JL , Saltiel AR . Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117: 175‐184, 2007.
 149. Lumeng CN , Deyoung SM , Saltiel AR . Macrophages block insulin action in adipocytes by altering expression of signaling and glucose transport proteins. Am J Physiol Endocrinol Metab 292: E166‐174, 2007.
 150. Luzi L , Perseghin G , Tambussi G , Meneghini E , Scifo P , Pagliato E , Del Maschio A , Testolin G , Lazzarin A . Intramyocellular lipid accumulation and reduced whole body lipid oxidation in HIV lipodystrophy. Am J Physiol Endocrinol Metab 284: E274‐280, 2003.
 151. Lysaght J , Allott EH , Donohoe CL , Howard JM , Pidgeon GP , Reynolds JV . T lymphocyte activation in visceral adipose tissue of patients with oesophageal adenocarcinoma. Br J Surg 98: 964‐974, 2011.
 152. Macallan DC , McNurlan MA , Kurpad AV , de Souza G , Shetty PS , Calder AG , Griffin GE . Whole body protein metabolism in human pulmonary tuberculosis and undernutrition: Evidence for anabolic block in tuberculosis. Clin Sci (Lond) 94: 321‐331, 1998.
 153. Macallan DC , McNurlan MA , Milne E , Calder AG , Garlick PJ , Griffin GE . Whole‐body protein turnover from leucine kinetics and the response to nutrition in human immunodeficiency virus infection. Am J Clin Nutr 61: 818‐826, 1995.
 154. Macallan DC , Noble C , Baldwin C , Jebb SA , Prentice AM , Coward WA , Sawyer MB , McManus TJ , Griffin GE . Energy expenditure and wasting in human immunodeficiency virus infection. N Engl J Med 333: 83‐88, 1995.
 155. Macias J , Gonzalez J , Tural C , Ortega‐Gonzalez E , Pulido F , Rubio R , Cifuentes C , Diaz‐Menendez M , Jou A , Rubio P , Burgos A , Pineda JA . Prevalence and factors associated with liver steatosis as measured by transient elastography with controlled attenuation parameter in HIV‐infected patients. AIDS 28: 1279‐1287, 2014.
 156. Mallal SA , John M , Moore CB , James IR , McKinnon EJ . Contribution of nucleoside analogue reverse transcriptase inhibitors to subcutaneous fat wasting in patients with HIV infection. AIDS 14: 1309‐1316, 2000.
 157. Mancini T , Secchiaroli G . Threats to identity: Lipodystrophy and identity changes in people with HIV/AIDS (PWA). Acta Biomed 86(Suppl 1): 29‐39, 2015.
 158. Mandard S , Patsouris D . Nuclear control of the inflammatory response in mammals by peroxisome proliferator‐activated receptors. PPAR Res 2013: 613864, 2013.
 159. Maughan RT , Feeney ER , Capel E , Capeau J , Domingo P , Giralt M , Lange JM , Phanuphak P , Cooper DA , Reiss P , Mallon PW , Group H‐S. Improved adipose tissue function with initiation of protease inhibitor‐only ART. J Antimicrob Chemother 71: 3212‐3221, 2016.
 160. Maurin T , Saillan‐Barreau C , Cousin B , Casteilla L , Doglio A , Penicaud L . Tumor necrosis factor‐alpha stimulates HIV‐1 production in primary culture of human adipocytes. Exp Cell Res 304: 544‐551, 2005.
 161. Maury E , Ehala‐Aleksejev K , Guiot Y , Detry R , Vandenhooft A , Brichard SM . Adipokines oversecreted by omental adipose tissue in human obesity. Am J Physiol Endocrinol Metab 293: E656‐665, 2007.
 162. McComsey GA , Daar ES , O'Riordan M , Collier AC , Kosmiski L , Santana JL , Fichtenbaum CJ , Fink H , Sax PE , Libutti DE , Gerschenson M . Changes in fat mitochondrial DNA and function in subjects randomized to abacavir‐lamivudine or tenofovir DF‐emtricitabine with atazanavir‐ritonavir or efavirenz: AIDS Clinical Trials Group study A5224s, substudy of A5202. J Infect Dis 207: 604‐611, 2013.
 163. McComsey GA , Kitch D , Sax PE , Tebas P , Tierney C , Jahed NC , Myers L , Melbourne K , Ha B , Daar ES . Peripheral and central fat changes in subjects randomized to abacavir‐lamivudine or tenofovir‐emtricitabine with atazanavir‐ritonavir or efavirenz: ACTG Study A5224s. Clin Infect Dis 53: 185‐196, 2011.
 164. McComsey GA , Paulsen DM , Lonergan JT , Hessenthaler SM , Hoppel CL , Williams VC , Fisher RL , Cherry CL , White‐Owen C , Thompson KA , Ross ST , Hernandez JE , Ross LL . Improvements in lipoatrophy, mitochondrial DNA levels and fat apoptosis after replacing stavudine with abacavir or zidovudine. AIDS 19: 15‐23, 2005.
 165. McCutchan JA , Marquie‐Beck JA , Fitzsimons CA , Letendre SL , Ellis RJ , Heaton RK , Wolfson T , Rosario D , Alexander TJ , Marra C , Ances BM , Grant I , Group C . Role of obesity, metabolic variables, and diabetes in HIV‐associated neurocognitive disorder. Neurology 78: 485‐492, 2012.
 166. Medina‐Gomez G , Gray SL , Yetukuri L , Shimomura K , Virtue S , Campbell M , Curtis RK , Jimenez‐Linan M , Blount M , Yeo GS , Lopez M , Seppanen‐Laakso T , Ashcroft FM , Oresic M , Vidal‐Puig A . PPAR gamma 2 prevents lipotoxicity by controlling adipose tissue expandability and peripheral lipid metabolism. PLoS Genet 3: e64, 2007.
 167. Meijer K , de Vries M , Al‐Lahham S , Bruinenberg M , Weening D , Dijkstra M , Kloosterhuis N , van der Leij RJ , van der Want H , Kroesen BJ , Vonk R , Rezaee F . Human primary adipocytes exhibit immune cell function: Adipocytes prime inflammation independent of macrophages. PLoS One 6: e17154, 2011.
 168. Melchior JC , Niyongabo T , Henzel D , Durack‐Bown I , Henri SC , Boulier A . Malnutrition and wasting, immunodepression, and chronic inflammation as independent predictors of survival in HIV‐infected patients. Nutrition 15: 865‐869, 1999.
 169. Melchior JC , Raguin G , Boulier A , Bouvet E , Rigaud D , Matheron S , Casalino E , Vilde JL , Vachon F , Coulaud JP . Resting energy expenditure in human immunodeficiency virus‐infected patients: Comparison between patients with and without secondary infections. Am J Clin Nutr 57: 614‐619, 1993.
 170. Melchior JC , Salmon D , Rigaud D , Leport C , Bouvet E , Detruchis P , Vilde JL , Vachon F , Coulaud JP , Apfelbaum M . Resting energy expenditure is increased in stable, malnourished HIV‐infected patients. Am J Clin Nutr 53: 437‐441, 1991.
 171. Minami R , Yamamoto M , Takahama S , Ando H , Miyamura T , Suematsu E . Comparison of the influence of four classes of HIV antiretrovirals on adipogenic differentiation: The minimal effect of raltegravir and atazanavir. J Infect Chemother 17: 183‐188, 2011.
 172. Mirani M , Elenkov I , Volpi S , Hiroi N , Chrousos GP , Kino T . HIV‐1 protein Vpr suppresses IL‐12 production from human monocytes by enhancing glucocorticoid action: Potential implications of Vpr coactivator activity for the innate and cellular immunity deficits observed in HIV‐1 infection. J Immunol 169: 6361‐6368, 2002.
 173. Miro O , Lopez S , Martinez E , Pedrol E , Milinkovic A , Deig E , Garrabou G , Casademont J , Gatell JM , Cardellach F . Mitochondrial effects of HIV infection on the peripheral blood mononuclear cells of HIV‐infected patients who were never treated with antiretrovirals. Clin Infect Dis 39: 710‐716, 2004.
 174. Miura T , Goto M , Hosoya N , Odawara T , Kitamura Y , Nakamura T , Iwamoto A . Depletion of mitochondrial DNA in HIV‐1‐infected patients and its amelioration by antiretroviral therapy. J Med Virol 70: 497‐505, 2003.
 175. Mohammed SS , Aghdassi E , Salit IE , Avand G , Sherman M , Guindi M , Heathcote JE , Allard JP . HIV‐positive patients with nonalcoholic fatty liver disease have a lower body mass index and are more physically active than HIV‐negative patients. J Acquir Immune Defic Syndr 45: 432‐438, 2007.
 176. Molina JM , Cahn P , Grinsztejn B , Lazzarin A , Mills A , Saag M , Supparatpinyo K , Walmsley S , Crauwels H , Rimsky LT , Vanveggel S , Boven K , group Es. Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment‐naive adults infected with HIV‐1 (ECHO): a phase 3 randomised double‐blind active‐controlled trial. Lancet 378: 238‐246, 2011.
 177. Mori MA , Raghavan P , Thomou T , Boucher J , Robida‐Stubbs S , Macotela Y , Russell SJ , Kirkland JL , Blackwell TK , Kahn CR . Role of microRNA processing in adipose tissue in stress defense and longevity. Cell Metab 16: 336‐347, 2012.
 178. Mori MA , Thomou T , Boucher J , Lee KY , Lallukka S , Kim JK , Torriani M , Yki‐Jarvinen H , Grinspoon SK , Cypess AM , Kahn CR . Altered miRNA processing disrupts brown/white adipocyte determination and associates with lipodystrophy. J Clin Invest 124: 3339‐3351, 2014.
 179. Morse CG , Voss JG , Rakocevic G , McLaughlin M , Vinton CL , Huber C , Hu X , Yang J , Huang da W , Logun C , Danner RL , Rangel ZG , Munson PJ , Orenstein JM , Rushing EJ , Lempicki RA , Dalakas MC , Kovacs JA . HIV infection and antiretroviral therapy have divergent effects on mitochondria in adipose tissue. J Infect Dis 205: 1778‐1787, 2012.
 180. Moure R , Domingo P , Gallego‐Escuredo JM , Villarroya J , Gutierrez MD , Mateo MG , Domingo JC , Giralt M , Villarroya F . Impact of elvitegravir on human adipocytes: Alterations in differentiation, gene expression and release of adipokines and cytokines. Antiviral Res 132: 59‐65, 2016.
 181. Moyle GJ , Baldwin C , Langroudi B , Mandalia S , Gazzard BG . A 48‐week, randomized, open‐label comparison of three abacavir‐based substitution approaches in the management of dyslipidemia and peripheral lipoatrophy. J Acquir Immune Defic Syndr 33: 22‐28, 2003.
 182. Mulligan K , Harris DR , Monte D , Stoszek S , Emmanuel P , Hardin DS , Kapogiannis BG , Worrell C , Meyer WA, III , Sleasman J , Wilson CM , Aldrovandi GM , Adolescent Trials Network 021 Protocol T. Obesity and dyslipidemia in behaviorally HIV‐infected young women: Adolescent Trials Network study 021. Clin Infect Dis 50: 106‐114, 2010.
 183. Mulligan K , Tai VW , Schambelan M . Cross‐sectional and longitudinal evaluation of body composition in men with HIV infection. J Acquir Immune Defic Syndr Hum Retrovirol 15: 43‐48, 1997.
 184. Munier S , Borjabad A , Lemaire M , Mariot V , Hazan U . In vitro infection of human primary adipose cells with HIV‐1: A reassessment. AIDS 17: 2537‐2539, 2003.
 185. Murata H , Hruz PW , Mueckler M . The mechanism of insulin resistance caused by HIV protease inhibitor therapy. J Biol Chem 275: 20251‐20254, 2000.
 186. Murti KG , Brown PS , Ratner L , Garcia JV . Highly localized tracks of human immunodeficiency virus type 1 Nef in the nucleus of cells of a human CD4+ T‐cell line. Proc Natl Acad Sci U S A 90: 11895‐11899, 1993.
 187. Nazli A , Chan O , Dobson‐Belaire WN , Ouellet M , Tremblay MJ , Gray‐Owen SD , Arsenault AL , Kaushic C . Exposure to HIV‐1 directly impairs mucosal epithelial barrier integrity allowing microbial translocation. PLoS Pathog 6: e1000852, 2010.
 188. Neels JG , Badeanlou L , Hester KD , Samad F . Keratinocyte‐derived chemokine in obesity: Expression, regulation, and role in adipose macrophage infiltration and glucose homeostasis. J Biol Chem 284: 20692‐20698, 2009.
 189. Newgard CB. Interplay between lipids and branched‐chain amino acids in development of insulin resistance. Cell Metab 15: 606‐614, 2012.
 190. Nguyen MT , Chen A , Lu WJ , Fan W , Li PP , Oh DY , Patsouris D . Regulation of chemokine and chemokine receptor expression by PPARgamma in adipocytes and macrophages. PLoS One 7: e34976, 2012.
 191. Nishimura S , Manabe I , Nagasaki M , Eto K , Yamashita H , Ohsugi M , Otsu M , Hara K , Ueki K , Sugiura S , Yoshimura K , Kadowaki T , Nagai R . CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 15: 914‐920, 2009.
 192. Nolan D , Hammond E , James I , McKinnon E , Mallal S . Contribution of nucleoside‐analogue reverse transcriptase inhibitor therapy to lipoatrophy from the population to the cellular level. Antivir Ther 8: 617‐626, 2003.
 193. Nolan D , Hammond E , Martin A , Taylor L , Herrmann S , McKinnon E , Metcalf C , Latham B , Mallal S . Mitochondrial DNA depletion and morphologic changes in adipocytes associated with nucleoside reverse transcriptase inhibitor therapy. AIDS 17: 1329‐1338, 2003.
 194. Onwubalili JK . Malnutrition among tuberculosis patients in Harrow, England. Eur J Clin Nutr 42: 363‐366, 1988.
 195. Orlando G , Guaraldi G , Zona S , Carli F , Bagni P , Menozzi M , Cocchi S , Scaglioni R , Ligabue G , Raggi P . Ectopic fat is linked to prior cardiovascular events in men with HIV. J Acquir Immune Defic Syndr 59: 494‐497, 2012.
 196. Otake K , Omoto S , Yamamoto T , Okuyama H , Okada H , Okada N , Kawai M , Saksena NK , Fujii YR . HIV‐1 Nef protein in the nucleus influences adipogenesis as well as viral transcription through the peroxisome proliferator‐activated receptors. AIDS 18: 189‐198, 2004.
 197. Palella FJ, Jr. , McKibben R , Post WS , Li X , Budoff M , Kingsley L , Witt MD , Jacobson LP , Brown TT . Anatomic fat depots and coronary plaque among human immunodeficiency virus‐infected and uninfected men in the multicenter AIDS cohort study. Open Forum Infect Dis 3: ofw098, 2016.
 198. Pallikkuth S , Mohan M . Adipose tissue: Sanctuary for HIV/SIV persistence and replication. Trends Microbiol 23: 748‐750, 2015.
 199. Pandolfi JB , Ferraro AA , Sananez I , Gancedo MC , Baz P , Billordo LA , Fainboim L , Arruvito L . ATP‐induced inflammation drives tissue‐resident Th17 cells in metabolically unhealthy obesity. J Immunol 196: 3287‐3296, 2016.
 200. Park TE , Mohamed A , Kalabalik J , Sharma R . Review of integrase strand transfer inhibitors for the treatment of human immunodeficiency virus infection. Expert Rev Anti Infect Ther 13: 1195‐1212, 2015.
 201. Pascual G , Sullivan AL , Ogawa S , Gamliel A , Perissi V , Rosenfeld MG , Glass CK . Anti‐inflammatory and antidiabetic roles of PPARgamma. Novartis Found Symp 286: 183‐196; discussion 196‐203, 2007.
 202. Paton NI , Macallan DC , Jebb SA , Noble C , Baldwin C , Pazianas M , Griffin GE . Longitudinal changes in body composition measured with a variety of methods in patients with AIDS. J Acquir Immune Defic Syndr Hum Retrovirol 14: 119‐127, 1997.
 203. Perez‐Matute P , Perez‐Martinez L , Blanco JR , Oteo JA . Neutral actions of Raltegravir on adipogenesis, glucose metabolism and lipolysis in 3T3‐L1 adipocytes. Curr HIV Res 9: 174‐179, 2011.
 204. Perez‐Matute P , Perez‐Martinez L , Blanco JR , Oteo JA . Role of mitochondria in HIV infection and associated metabolic disorders: Focus on nonalcoholic fatty liver disease and lipodystrophy syndrome. Oxid Med Cell Longev 2013: 493413, 2013.
 205. Perez‐Molina JA , Domingo P , Martinez 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 62: 234‐245, 2008.
 206. Persson A . Facing HIV: Body shape change and the (in)visibility of illness. Med Anthropol 24: 237‐264, 2005.
 207. Podany AT , Scarsi KK , Fletcher CV . Comparative clinical pharmacokinetics and pharmacodynamics of HIV‐1 integrase strand transfer inhibitors. Clin Pharmacokinet, 2016.
 208. Podzamczer D , Ferrer E , Sanchez P , Gatell JM , Crespo M , Fisac C , Lonca M , Sanz J , Niubo J , Veloso S , Llibre JM , Barrufet P , Ribas MA , Merino E , Ribera E , Martinez‐Lacasa J , Alonso C , Aranda M , Pulido F , Berenguer J , Delegido A , Pedreira JD , Lerida A , Rubio R , del Rio L , Team AS . Less lipoatrophy and better lipid profile with abacavir as compared to stavudine: 96‐week results of a randomized study. J Acquir Immune Defic Syndr 44: 139‐147, 2007.
 209. Poon B , Grovit‐Ferbas K , Stewart SA , Chen IS . Cell cycle arrest by Vpr in HIV‐1 virions and insensitivity to antiretroviral agents. Science 281: 266‐269, 1998.
 210. Powanda MC , Beisel WR . Metabolic effects of infection on protein and energy status. J Nutr 133: 322S‐327S, 2003.
 211. Price J , Hoy J , Ridley E , Nyulasi I , Paul E , Woolley I . Changes in the prevalence of lipodystrophy, metabolic syndrome and cardiovascular disease risk in HIV‐infected men. Sex Health 12: 240‐248, 2015.
 212. Ramanathan S , Mathias AA , German P , Kearney BP . Clinical pharmacokinetic and pharmacodynamic profile of the HIV integrase inhibitor elvitegravir. Clin Pharmacokinet 50: 229‐244, 2011.
 213. Rasmussen TA , Tolstrup M , Brinkmann CR , Olesen R , Erikstrup C , Solomon A , Winckelmann A , Palmer S , Dinarello C , Buzon M , Lichterfeld M , Lewin SR , Ostergaard L , Sogaard OS . Panobinostat, a histone deacetylase inhibitor, for latent‐virus reactivation in HIV‐infected patients on suppressive antiretroviral therapy: A phase 1/2, single group, clinical trial. The lancet HIV 1: e13‐21, 2014.
 214. Reeds DN , Mittendorfer B , Patterson BW , Powderly WG , Yarasheski KE , Klein S . Alterations in lipid kinetics in men with HIV‐dyslipidemia. Am J Physiol Endocrinol Metab 285: E490‐E497, 2003.
 215. Reingold J , Wanke C , Kotler D , Lewis C , Tracy R , Heymsfield S , Tien P , Bacchetti P , Scherzer R , Grunfeld C , Shlipak M . Association of HIV infection and HIV/HCV coinfection with C‐reactive protein levels: The fat redistribution and metabolic change in HIV infection (FRAM) study. J Acquir Immune Defic Syndr 48: 142‐148, 2008.
 216. Reynes J , Trinh R , Pulido F , Soto‐Malave R , Gathe J , Qaqish R , Tian M , Fredrick L , Podsadecki T , Norton M , Nilius A . Lopinavir/ritonavir combined with raltegravir or tenofovir/emtricitabine in antiretroviral‐naive subjects: 96‐week results of the PROGRESS study. AIDS Res Hum Retroviruses 29: 256‐265, 2013.
 217. Riddler SA , Haubrich R , DiRienzo AG , Peeples L , Powderly WG , Klingman KL , Garren KW , George T , Rooney JF , Brizz B , Lalloo UG , Murphy RL , Swindells S , Havlir D , Mellors JW , Team ACTGSA. Class‐sparing regimens for initial treatment of HIV‐1 infection. N Engl J Med 358: 2095‐2106, 2008.
 218. Rockstroh JK , Lennox JL , Dejesus E , Saag MS , Lazzarin A , Wan H , Walker ML , Xu X , Zhao J , Teppler H , Dinubile MJ , Rodgers AJ , Nguyen BY , Leavitt R , Sklar P , Investigators S . Long‐term treatment with raltegravir or efavirenz combined with tenofovir/emtricitabine for treatment‐naive human immunodeficiency virus‐1‐infected patients: 156‐week results from STARTMRK. Clin Infect Dis 53: 807‐816, 2011.
 219. Romani B , Engelbrecht S , Glashoff RH . Functions of Tat: The versatile protein of human immunodeficiency virus type 1. J Gen Virol 91: 1‐12, 2010.
 220. Rudich A , Ben‐Romano R , Etzion S , Bashan N . Cellular mechanisms of insulin resistance, lipodystrophy and atherosclerosis induced by HIV protease inhibitors. Acta Physiol Scand 183: 75‐88, 2005.
 221. Ruiz L , Negredo E , Domingo P , Paredes R , Francia E , Balague M , Gel S , Bonjoch A , Fumaz CR , Johnston S , Romeu J , Lange J , Clotet B , Spanish Lipodystrophy G . Antiretroviral treatment simplification with nevirapine in protease inhibitor‐experienced patients with hiv‐associated lipodystrophy: 1‐year prospective follow‐up of a multicenter, randomized, controlled study. J Acquir Immune Defic Syndr 27: 229‐236, 2001.
 222. Saillan‐Barreau C , Tabbakh O , Chavoin JP , Casteilla L , Penicaud L . Drug‐specific effect of nelfinavir and stavudine on primary culture of human preadipocytes. J Acquir Immune Defic Syndr 48: 20‐25, 2008.
 223. Saint‐Marc T , Touraine JL . The effects of discontinuing stavudine therapy on clinical and metabolic abnormalities in patients suffering from lipodystrophy. AIDS 13: 2188‐2189, 1999.
 224. Sankaran S , George MD , Reay E , Guadalupe M , Flamm J , Prindiville T , Dandekar S . Rapid onset of intestinal epithelial barrier dysfunction in primary human immunodeficiency virus infection is driven by an imbalance between immune response and mucosal repair and regeneration. J Virol 82: 538‐545, 2008.
 225. Sapountzi V , Logan IR , Robson CN . Cellular functions of TIP60. Int J Biochem Cell Biol 38: 1496‐1509, 2006.
 226. Saves M , Raffi F , Capeau J , Rozenbaum W , Ragnaud JM , Perronne C , Basdevant A , Leport C , Chene G , Antiproteases Cohorte Study G. Factors related to lipodystrophy and metabolic alterations in patients with human immunodeficiency virus infection receiving highly active antiretroviral therapy. Clin Infect Dis 34: 1396‐1405, 2002.
 227. Sekhar RV , Jahoor F , Pownall HJ , Rehman K , Gaubatz J , Iyer D , Balasubramanyam A . Severely dysregulated disposal of postprandial triacylglycerols exacerbates hypertriacylglycerolemia in HIV lipodystrophy syndrome. Am J Clin Nutr 81: 1405‐1410, 2005.
 228. Sekhar RV , Jahoor F , White AC , Pownall HJ , Visnegarwala F , Rodriguez‐Barradas MC , Sharma M , Reeds PJ , Balasubramanyam A . Metabolic basis of HIV‐lipodystrophy syndrome. Am J Physiol Endocrinol Metab 283: E332‐337, 2002.
 229. Semple RK , Chatterjee VK , O'Rahilly S . PPAR gamma and human metabolic disease. J Clin Invest 116: 581‐589, 2006.
 230. Shah TJ , Leik CE , Walsh SW . Neutrophil infiltration and systemic vascular inflammation in obese women. Reprod Sci 17: 116‐124, 2010.
 231. Sharpstone DR , Murray CP , Ross HM , Hancock MR , Phelan MS , Crane RC , Menzies IS , Reaveley DA , Lepri AC , Nelson MR , Gazzard BG . Energy balance in asymptomatic HIV infection. AIDS 10: 1377‐1384, 1996.
 232. Sherman MP , de Noronha CM , Pearce D , Greene WC . Human immunodeficiency virus type 1 Vpr contains two leucine‐rich helices that mediate glucocorticoid receptor coactivation independently of its effects on G(2) cell cycle arrest. J Virol 74: 8159‐8165, 2000.
 233. Shevitz AH , Knox TA , Spiegelman D , Roubenoff R , Gorbach SL , Skolnik PR . Elevated resting energy expenditure among HIV‐seropositive persons receiving highly active antiretroviral therapy. AIDS 13: 1351‐1357, 1999.
 234. Shields M , Carroll MD , Ogden CL . Adult obesity prevalence in Canada and the United States. In: NCHS data brief, no 56. Hyattsville, MD: National Center for Health Statistics, 2011.
 235. Shikuma CM , Gangcuangco LM , Killebrew DA , Libutti DE , Chow DC , Nakamoto BK , Liang CY , Milne CI , Ndhlovu LC , Barbour JD , Shiramizu BT , Gerschenson M . The role of HIV and monocytes/macrophages in adipose tissue biology. J Acquir Immune Defic Syndr 65: 151‐159, 2014.
 236. Shlay JC , Bartsch G , Peng G , Wang J , Grunfeld C , Gibert CL , Visnegarwala F , Raghavan SS , Xiang Y , Farrough M , Perry HE , Kotler D , El‐Sadr WM . Long‐term body composition and metabolic changes in antiretroviral naive persons randomized to protease inhibitor‐, nonnucleoside reverse transcriptase inhibitor‐, or protease inhibitor plus nonnucleoside reverse transcriptase inhibitor‐based strategy. J Acquir Immune Defic Syndr 44: 506‐517, 2007.
 237. Shrivastav S , Kino T , Cunningham T , Ichijo T , Schubert U , Heinklein P , Chrousos GP , Kopp JB . Human immunodeficiency virus (HIV)‐1 viral protein R suppresses transcriptional activity of peroxisome proliferator‐activated receptor {gamma} and inhibits adipocyte differentiation: Implications for HIV‐associated lipodystrophy. Mol Endocrinol 22: 234‐247, 2008.
 238. Shrivastav S , Zhang L , Okamoto K , Lee H , Lagranha C , Abe Y , Balasubramanyam A , Lopaschuk GD , Kino T , Kopp JB . HIV‐1 Vpr enhances PPARbeta/delta‐mediated transcription, increases PDK4 expression, and reduces PDC activity. Mol Endocrinol 27: 1564‐1576, 2013.
 239. Stankov MV , Lucke T , Das AM , Schmidt RE , Behrens GM . Mitochondrial DNA depletion and respiratory chain activity in primary human subcutaneous adipocytes treated with nucleoside analogue reverse transcriptase inhibitors. Antimicrob Agents Chemother 54: 280‐287, 2010.
 240. Stanley TL , Grinspoon SK . Body composition and metabolic changes in HIV‐infected patients. J Infect Dis 205(Suppl 3): S383‐390, 2012.
 241. Staszewski S , Morales‐Ramirez J , Tashima KT , Rachlis A , Skiest D , Stanford J , Stryker R , Johnson P , Labriola DF , Farina D , Manion DJ , Ruiz NM . Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV‐1 infection in adults. Study 006 Team. N Engl J Med 341: 1865‐1873, 1999.
 242. Stienstra R , Duval C , Keshtkar S , van der Laak J , Kersten S , Muller M . Peroxisome proliferator‐activated receptor gamma activation promotes infiltration of alternatively activated macrophages into adipose tissue. J Biol Chem 283: 22620‐22627, 2008.
 243. Sulyok M , Makara M , Rupnik Z , Ferenci T , Ujhelyi E , Kormos L , Gerlei Z , Szlavik J , Horvath G , Valyi‐Nagy I . Hepatic steatosis in individuals living with HIV measured by controlled attenuation parameter: A cross‐sectional study. Eur J Gastroenterol Hepatol 27: 679‐685, 2015.
 244. Sutherland LN , Capozzi LC , Turchinsky NJ , Bell RC , Wright DC . Time course of high‐fat diet‐induced reductions in adipose tissue mitochondrial proteins: Potential mechanisms and the relationship to glucose intolerance. Am J Physiol Endocrinol Metab 295: E1076‐1083, 2008.
 245. Suttmann U , Ockenga J , Selberg O , Hoogestraat L , Deicher H , Muller MJ . Incidence and prognostic value of malnutrition and wasting in human immunodeficiency virus‐infected outpatients. J Acquir Immune Defic Syndr Hum Retrovirol 8: 239‐246, 1995.
 246. Talukdar S , Oh da Y , Bandyopadhyay G , Li D , Xu J , McNelis J , Lu M , Li P , Yan Q , Zhu Y , Ofrecio J , Lin M , Brenner MB , Olefsky JM . Neutrophils mediate insulin resistance in mice fed a high‐fat diet through secreted elastase. Nat Med 18: 1407‐1412, 2012.
 247. Tang T , Zhang J , Yin J , Staszkiewicz J , Gawronska‐Kozak B , Jung DY , Ko HJ , Ong H , Kim JK , Mynatt R , Martin RJ , Keenan M , Gao Z , Ye J . Uncoupling of inflammation and insulin resistance by NF‐kappaB in transgenic mice through elevated energy expenditure. J Biol Chem 285: 4637‐4644, 2010.
 248. Tavassoli N , Bagheri H , Sommet A , Delpierre C , Marion‐Latard F , Massip P , Aquilina C , Bonnet E , Obadia M , Labau E , Montastruc JL , Bernard J . Effects of discontinuing stavudine or protease inhibitor therapy on human immunodeficiency virus‐related fat redistribution evaluated by dual‐energy x‐ray absorptiometry. Pharmacotherapy 26: 154‐161, 2006.
 249. Thewissen MM , Damoiseaux JG , Duijvestijn AM , van Greevenbroek MM , van der Kallen CJ , Feskens EJ , Blaak EE , Schalkwijk CG , Stehouwer CD , Cohen Tervaert JW , Ferreira I . Abdominal fat mass is associated with adaptive immune activation: The CODAM Study. Obesity (Silver Spring) 19: 1690‐1698, 2011.
 250. Thiara DK , Liu CY , Raman F , Mangat S , Purdy JB , Duarte HA , Schmidt N , Hur J , Sibley CT , Bluemke DA , Hadigan C . Abnormal myocardial function is related to myocardial steatosis and diffuse myocardial fibrosis in HIV‐infected adults. J Infect Dis 212: 1544‐1551, 2015.
 251. Tien PC , Cole SR , Williams CM , Li R , Justman JE , Cohen MH , Young M , Rubin N , Augenbraun M , Grunfeld C . Incidence of lipoatrophy and lipohypertrophy in the women's interagency HIV study. J Acquir Immune Defic Syndr 34: 461‐466, 2003.
 252. Tilg H , Moschen AR . Inflammatory mechanisms in the regulation of insulin resistance. Mol Med 14: 222‐231, 2008.
 253. Torriani M , Fitch K , Stavrou E , Bredella MA , Lim R , Sass CA , Cypess AM , Grinspoon S . Deiodinase 2 expression is increased in dorsocervical fat of patients with HIV‐associated lipohypertrophy syndrome. J Clin Endocrinol Metab 97: E602‐607, 2010.
 254. Torriani M , Srinivasa S , Fitch KV , Thomou T , Wong K , Petrow E , Kahn CR , Cypess AM , Grinspoon SK . Dysfunctional subcutaneous fat with reduced dicer and brown adipose tissue gene expression in HIV‐infected patients. J Clin Endocrinol Metab 101: 1225‐1234, 2016.
 255. Torriani M , Thomas BJ , Barlow RB , Librizzi J , Dolan S , Grinspoon S . Increased intramyocellular lipid accumulation in HIV‐infected women with fat redistribution. J Appl Physiol (1985) 100: 609‐614, 2006.
 256. Torriani M , Zanni MV , Fitch K , Stavrou E , Bredella MA , Lim R , Cypess AM , Grinspoon S . Increased FDG uptake in association with reduced extremity fat in HIV patients. Antivir Ther 18: 243‐248, 2013.
 257. Toyoda T , Kamei Y , Kato H , Sugita S , Takeya M , Suganami T , Ogawa Y . Effect of peroxisome proliferator‐activated receptor‐alpha ligands in the interaction between adipocytes and macrophages in obese adipose tissue. Obesity (Silver Spring) 16: 1199‐1207, 2008.
 258. Travers RL , Motta AC , Betts JA , Bouloumie A , Thompson D . The impact of adiposity on adipose tissue‐resident lymphocyte activation in humans. Int J Obes (Lond) 39: 762‐769, 2015.
 259. Tripathy MK , Mitra D . Differential modulation of mitochondrial OXPHOS system during HIV‐1 induced T‐cell apoptosis: Up regulation of Complex‐IV subunit COX‐II and its possible implications. Apoptosis 15: 28‐40, 2010.
 260. van Beekum O , Brenkman AB , Grontved L , Hamers N , van den Broek NJ , Berger R , Mandrup S , Kalkhoven E . The adipogenic acetyltransferase Tip60 targets activation function 1 of peroxisome proliferator‐activated receptor gamma. Endocrinology 149: 1840‐1849, 2008.
 261. van Lettow M , van der Meer JW , West CE , van Crevel R , Semba RD . Interleukin‐6 and human immunodeficiency virus load, but not plasma leptin concentration, predict anorexia and wasting in adults with pulmonary tuberculosis in Malawi. J Clin Endocrinol Metab 90: 4771‐4776, 2005.
 262. Vernochet C , Azoulay S , Duval D , Guedj R , Cottrez F , Vidal H , Ailhaud G , Dani C . Human immunodeficiency virus protease inhibitors accumulate into cultured human adipocytes and alter expression of adipocytokines. J Biol Chem 280: 2238‐2243, 2005.
 263. Vidal F , Domingo P , Villarroya F , Giralt M , Lopez‐Dupla M , Gutierrez M , Gallego‐Escuredo JM , Peraire J , Vilades C , Veloso S , Mateo G , Guallar JP , Richart C . Adipogenic/lipid, inflammatory, and mitochondrial parameters in subcutaneous adipose tissue of untreated HIV‐1‐infected long‐term nonprogressors: Significant alterations despite low viral burden. J Acquir Immune Defic Syndr 61: 131‐137, 2012.
 264. Viengchareun S , Caron M , Auclair M , Kim MJ , Frachon P , Capeau J , Lombes M , Lombes A . Mitochondrial toxicity of indinavir, stavudine and zidovudine involves multiple cellular targets in white and brown adipocytes. Antivir Ther 12: 919‐929, 2007.
 265. Vuille‐Lessard E , Lebouche B , Lennox L , Routy JP , Costiniuk CT , Pexos C , Giannakis A , Szabo J , Klein MB , Sebastiani G . Nonalcoholic fatty liver disease diagnosed by transient elastography with controlled attenuation parameter in unselected HIV monoinfected patients. AIDS 30: 2635‐2643, 2016.
 266. Wagner KD , Wagner N . Peroxisome proliferator‐activated receptor beta/delta (PPARbeta/delta) acts as regulator of metabolism linked to multiple cellular functions. Pharmacol Ther 125: 423‐435, 2010.
 267. Walker UA , Auclair M , Lebrecht D , Kornprobst M , Capeau J , Caron M . Uridine abrogates the adverse effects of antiretroviral pyrimidine analogues on adipose cell functions. Antivir Ther 11: 25‐34, 2006.
 268. Walker UA , Bickel M , Lutke Volksbeck SI , Ketelsen UP , Schofer H , Setzer B , Venhoff N , Rickerts V , Staszewski S . Evidence of nucleoside analogue reverse transcriptase inhibitor–associated genetic and structural defects of mitochondria in adipose tissue of HIV‐infected patients. J Acquir Immune Defic Syndr 29: 117‐121, 2002.
 269. Walker UA , Lebrecht D , Reichard W , Kirschner J , Bisse E , Iversen L , Venhoff AC , Venhoff N . Zidovudine induces visceral mitochondrial toxicity and intra‐abdominal fat gain in a rodent model of lipodystrophy. Antivir Ther 19: 783‐792, 2014.
 270. Wang T , Jiang Z , Hou W , Li Z , Cheng S , Green LA , Wang Y , Wen X , Cai L , Clauss M , Wang Z . HIV Tat protein affects circadian rhythmicity by interfering with the circadian system. HIV Med 15: 565‐570, 2014.
 271. Weber FP , Kirkness WR . A note on body‐weight in relation to pulmonary tuberculosis. Br Med J 1: 142‐143, 1909.
 272. Wei DG , Chiang V , Fyne E , Balakrishnan M , Barnes T , Graupe M , Hesselgesser J , Irrinki A , Murry JP , Stepan G , Stray KM , Tsai A , Yu H , Spindler J , Kearney M , Spina CA , McMahon D , Lalezari J , Sloan D , Mellors J , Geleziunas R , Cihlar T . Histone deacetylase inhibitor romidepsin induces HIV expression in CD4 T cells from patients on suppressive antiretroviral therapy at concentrations achieved by clinical dosing. PLoS Pathog 10: e1004071, 2014.
 273. Weisberg SP , McCann D , Desai M , Rosenbaum M , Leibel RL , Ferrante AW, Jr . Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112: 1796‐1808, 2003.
 274. Westendorp MO , Frank R , Ochsenbauer C , Stricker K , Dhein J , Walczak H , Debatin KM , Krammer PH . Sensitization of T cells to CD95‐mediated apoptosis by HIV‐1 Tat and gp120. Nature 375: 497‐500, 1995.
 275. Wilkin A , Pozniak AL , Morales‐Ramirez J , Lupo SH , Santoscoy M , Grinsztejn B , Ruxrungtham K , Rimsky LT , Vanveggel S , Boven K , Group TCS . Long‐term efficacy, safety, and tolerability of rilpivirine (RPV, TMC278) in HIV type 1‐infected antiretroviral‐naive patients: Week 192 results from a phase IIb randomized trial. AIDS Res Hum Retroviruses 28: 437‐446, 2012.
 276. Winer DA , Winer S , Shen L , Wadia PP , Yantha J , Paltser G , Tsui H , Wu P , Davidson MG , Alonso MN , Leong HX , Glassford A , Caimol M , Kenkel JA , Tedder TF , McLaughlin T , Miklos DB , Dosch HM , Engleman EG . B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat Med 17: 610‐617, 2011.
 277. Winer S , Chan Y , Paltser G , Truong D , Tsui H , Bahrami J , Dorfman R , Wang Y , Zielenski J , Mastronardi F , Maezawa Y , Drucker DJ , Engleman E , Winer D , Dosch HM . Normalization of obesity‐associated insulin resistance through immunotherapy. Nat Med 15: 921‐929, 2009.
 278. Wu H , Ghosh S , Perrard XD , Feng L , Garcia GE , Perrard JL , Sweeney JF , Peterson LE , Chan L , Smith CW , Ballantyne CM . T‐cell accumulation and regulated on activation, normal T cell expressed and secreted upregulation in adipose tissue in obesity. Circulation 115: 1029‐1038, 2007.
 279. Xu H , Barnes GT , Yang Q , Tan G , Yang D , Chou CJ , Sole J , Nichols A , Ross JS , Tartaglia LA , Chen H . Chronic inflammation in fat plays a crucial role in the development of obesity‐related insulin resistance. J Clin Invest 112: 1821‐1830, 2003.
 280. Yarasheski KE , Zachwieja JJ , Gischler J , Crowley J , Horgan MM , Powderly WG . Increased plasma gln and Leu Ra and inappropriately low muscle protein synthesis rate in AIDS wasting. Am J Physiol 275: E577‐583, 1998.
 281. Yeop Han C , Kargi AY , Omer M , Chan CK , Wabitsch M , O'Brien KD , Wight TN , Chait A . Differential effect of saturated and unsaturated free fatty acids on the generation of monocyte adhesion and chemotactic factors by adipocytes: Dissociation of adipocyte hypertrophy from inflammation. Diabetes 59: 386‐396, 2010.
 282. Yuh B , Tate J , Butt AA , Crothers K , Freiberg M , Leaf D , Logeais M , Rimland D , Rodriguez‐Barradas MC , Ruser C , Justice AC . Weight change after antiretroviral therapy and mortality. Clin Infect Dis 60: 1852‐1859, 2015.
 283. Zhang SM , Song M , Yang TY , Fan R , Liu XD , Zhou PK . HIV‐1 Tat impairs cell cycle control by targeting the Tip60, Plk1 and cyclin B1 ternary complex. Cell Cycle 11: 1217‐1234, 2012.
 284. Zurier RB , Rossetti RG , Seiler CM , Laposata M . Human peripheral blood T lymphocyte proliferation after activation of the T cell receptor: Effects of unsaturated fatty acids. Prostaglandins Leukot Essent Fatty Acids 60: 371‐375, 1999.

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John R. Koethe. Adipose Tissue in HIV Infection. Compr Physiol 2017, 7: 1339-1357. doi: 10.1002/cphy.c160028