Premature and accelerated aging: HIV or HAART?

Frontiers in Genetics

Volumn 3, Issue JAN, 2013, Pages

  Smith, Reuben L ^a   de Boer, Richard ^a   Brul, Stanley ^a   Budovskaya, Yelena ^a   van der Spek, Hans ^a  

^a UNIVERSITY OF AMSTERDAM   (Netherlands)

Author keywords

Antiretroviral; C. Elegans; HAART; HIV; Immunosenescence; Mitochondria; NRTI; Premature and accelerated aging

Indexed keywords

CAENORHABDITIS ELEGANS; HUMAN IMMUNODEFICIENCY VIRUS;

EID: 84876176102     PISSN: None     EISSN: 16648021     Source Type: Journal    
DOI: 10.3389/fgene.2012.00328     Document Type: Review

References (115)

1. Adamson, C. S. (2012). Protease-mediated maturation of HIV: inhibitors of protease and the maturation process. Mol. Biol. Int. 2012, 604261.
2. Addo, M. G., Cossard, R., Pichard, D., Obiri-Danso, K., Rotig, A., and Dela-hodde, A. (2010). Caenorhabditis elegans, a pluricellular model organism to screen new genes involved in mitochondrial genome maintenance. Biochim. Biophys. Acta 1802, 765-773.
3. Anthony, I. C, Ramage, S. N., Carnie, E W., Simmonds, P., and Bell, J. E. (2006). Accelerated Tau deposition in the brains of individuals infected with human immunodeficiency virus-1 before and after the advent of highly active anti-retroviral therapy. Acta Neuropathol. 111,529-538.
4. Apostolova, N., Blas-Garcia, A., and Esplugues, J. V. (2011a). Mitochondrial interference by anti-HIV drugs: mechanisms beyond Pol-y inhibition. Trends Pharmacol Sci. 32, 715-725.
5. Apostolova, N., Gomez-sucerquia, L. J., Gortat, A., Blas-garcia, A., and Esplugues, J. V (2011b). Autophagy as a rescue mechanism in efavirenz-induced mitochondrial dysfunction, a lesson from hepatic cells. Autophagy 7, 1-3.
6. Appay, V, and Sauce, D. (2008). Immune activation and inflammation in HIV-1 infection: causes and consequences. J. Pathol 214, 231-241.
7. Badley, A. D. (2005). In vitro and in vivo effects of HIV protease inhibitors on apoptosis. Cell death and differentiation Cell Death Differ. 12(Suppl. 1), 924-931.
8. Baliga, R. S., Liu, C, Hoyt, D. G., Chaves, A. A., and Bauer, J. A. (2004). Vascular endothelial toxicity induced by HIV protease inhibitor: evidence of oxidant-related dysfunction and apoptosis. Cardiovasc. Toxicol. 4, 199-206.
9. Ben-Romano, R., Rudich, A., Etzion, S., Potashnik, R., Kagan, E., Green-baum, U., et al. (2006). Nelfinavir induces adipocyte insulin resistance through the induction of oxidative stress: differential protective effect of antioxidant agents. Antivir. Ther. 11, 1051-1060.
10. Bess, A. S., Crocker, T. L, Ryde, I. T., and Meyer, J. N. (2012). Mitochondrial dynamics and autophagy aid in removal of persistent mitochondrial DNA damage in Caenorhabditis elegans. Nucleic Acids Res. 40, 7916- 7931.
11. Blasco, M. A. (2007). Telomere length, stem cells and aging. Nat. Chem. Biol. 3, 640-649.
12. Blas-Garcia, A., Apostolova, N., and Esplugues, J. V (2011). Oxidative stress and mitochondrial impairment after treatment with anti-HIV drugs: clinical implications. Curr. Pharm. Des. 17,4076-4086.
13. Brand, M. D. (2010). The sites and topology of mitochondrial superox-ide production. Exp. Gerontol 45, 466-472.
14. Bratic, I., Hench, J., and Trifunovic, A. (2010). Caenorhabditis elegans as a model system for mtDNA replication defects. Methods 51, 437-443.
15. Brinkman, K., ter Hofstede, H. J., Burger, D. M., Smeitink, J. A., and Koopmans, P. P. (1998). Adverse effects of reverse transcrip-tase inhibitors: mitochondrial toxi-city as common pathway. AIDS 12, 1735-1744.
16. Camacho, R., and Teofilo, E. (2011). Antiretroviral therapy in treatment-nai've patients with HIV infection. Curr. Opin. HTV AIDS 6(Suppl. 1), S3-S11.
17. Caron, M., Auclair, M., Donadille, B., Bereziat, V., Guerci, B., Laville, M., et al. (2007). Human lipodystrophies linked to mutations in A-type lamins and to HIV protease inhibitor therapy are both associated with prelamin A accumulation, oxidative stress and premature cellular senescence. Cell Death. Differ. 14, 1759-1767.
18. Caron, M., Auclairt, M., Vissian, A., Vigouroux, C, and Capeau, J. (2008). Contribution of mitochondrial dysfunction and oxidative stress to cellular premature senescence induced by antiretroviral thymidine analogues. Antivir. Ther. 13,27-38.
19. Caron-Debarle, M., Lagathu, C, Boc-cara, E, Vigouroux, C, and Capeau, J. (2010). HIV-associated lipodystro-phy: from fat injury to premature aging. TrendsMol Med. 16,218-229.
20. Chandra, S., Mondal, D., and Agrawal, K. C. (2009). HIV-1 protease inhibitor induced oxidative stress suppresses glucose stimulated insulin release: protection with thy-moquinone. Exp. Biol. Med. 234, 442-453.
21. Chen, H., Vermulst, M., Wang, Y. E., Chomyn, A., Prolla, T. A., McCaf-fery, J. M., et al. (2010). Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations. Cell 141, 280-289.
22. Cihlar, T., and Ray, A. S. (2010). Nucle-oside and nucleotide HIV reverse transcriptase inhibitors: 25 years after zidovudine. Antivir. Res. 85, 39-58.
23. Cline, S. D. (2012). Mitochondrial DNA damage and its consequences for mitochondrial gene expression. Biochim. Biophys. Ada 1819, 979-991.
24. Cote, H. C. F., Brumme, Z. L., Craib, K. J. P., Alexander, C. S., Wyn-hoven, B., Ting, L., et al. (2002). Changes in mitochondrial DNA as a marker of nucleoside toxicityin HIV-infected patients. N. Engl. J. Med. 346, 811-820.
25. Culetto, E., and Sattelle, D. B. (2000). A role for Caenorhabditis elegans in understanding the function and interactions of human disease genes. Hum. Mol. Genet. 9, 869-877.
26. d'Amati, G., and Lewis, W. (1994). Zidovudine causes early increases in mitochondrial ribonucleic acid abundance and induces ultrastruc-tural changes in cultured mouse muscle cells. Lab. Invest. 71, 879-884.
27. Day, B. J., and Lewis, W. (2004). Oxidative stress in NRTI-induced toxic-ity: evidence from clinical experience and experiments in vitro and in vivo. Cardiovasc. Toxicol. 4, 207-216.
28. De Clercq, E. (2004). Non-nucleoside reverse transcriptase inhibitors (NNRTIs): past, present, and future. Chetn. Biodivers. 1,44-64.
29. Deeks, S. G., and Phillips, A. N. (2009). HIV infection, antiretroviral treatment, ageing, and non-AIDS related morbidity. BMJ 338, a3172.
30. Deeks, S. G., Verdin, E., and McCune, J. M. (2012). Immunosenescence and HIV. Curr. Opin. Immunol 24, 501-506.
31. de la Asuncion, J. G., del Olmo, M. L., Sastre, J., Millan, A., Pellin, A., Pallardo, E V, et al. (1998). AZT treatment induces molecular and ultrastructural oxidative damage to muscle mitochondria. Prevention by antioxidant vitamins. J. Clin. Invest. 102,4-9.
32. Deng, W., Baki, L., Yin, J., Zhou, H., and Baumgarten, C. M. (2010). HIV protease inhibitors elicit volume-sensitive Cl- current in cardiac myocytes via mitochondrial ROS. J. Mol. Cell. Cardiol. 49, 746-752.
33. Desai, S., and Landay, A. (2010). Early immune senescence in HIV disease. Curr. HIV/AIDS Rep. 7,4-10.
34. Desler, C, Hansen, T. L., Frederik-sen, J. B., Marcker, M. L, Singh, K. K., and Juel Rasmussen, L. (2012). Is there a link between mitochondrial reserve respiratory capacity and aging? J. Aging Res. 2012, 192503.
35. Desler, C, Marcker, M. L., Singh, K. K., and Rasmussen, L. J. (2011). The importance of mitochondrial DNA in aging and cancer. J. Aging Res. 2011, 407536.
36. Dock, J. N., and Effros, R. B. (2011). Role of CD8 T cell replicative senescence in human aging and in HIV-mediated immunosenescence. Aging and Dis. 2, 382-397.
37. Dybul, M., Fauci, A. S., Bartlett, J. G., Kaplan, J. E., and Pau, A. K. (2002). Guidelines for using antiretroviral agents among HIV-infected adults and adolescents. Ann. Intern. Med. 137(5 Pt 2), 381-433.
38. Effros, R. B., Fletcher, C. V, Gebo, K., Halter, J. B., Hazzard, W. R., Home, F. M., et al. (2011). Workshop on HIV infection and aging: what is known and future research directions. Clin. Infect. Dis. 47, 542-553.
39. Faraj, A., Fowler, D. A., Bridges, E. G., and Sommadossi, J. P. (1994). Effects of 2',3'-dideoxynucleosides on proliferation and differentiation of human pluripotent progenitors in liquid culture and their effects on mitochondrial DNA synthesis. Antimicrob. Agents Chemother. 38, 924-930.
40. Ferrando-Martinez, S., Ruiz-Mateos, E., Romero-Sanchez, M. C, Munoz-Fernandez, M. A., Viciana, P., Genebat, M., et al. (2011). HIV infection-related premature immunosenescence: high rates of immune exhaustion after short time of infection. Curr. HIV Res. 9, 289-294.
41. Fisher, M., and Cooper, V (2012). HIV and ageing: premature ageing or premature conclusions? Curr. Opin. Infect. Dis. 25, 1-3.
42. Fleischman, A., Johnsen, S., Systrom, D. M., Hrovat, M., Farrar, C. T., Frontera, W, et al. (2007). Effects of a nucleoside reverse transcriptase inhibitor, stavudine, on glucose disposal and mitochondrial function in muscle of healthy adults. Am. J. Phys-iol. Endocrinol. Metab. 292, E1666-E1673.
43. Freund, A., Orjalo, A. V, Desprez, P. Y., and Campisi, J. (2010). Inflammatory networks during cellular senescence: causes and consequences. Trends Mol. Med. 16,238-246.
44. Galloway, C. A., and Yoon, Y. (2012). Mitochondrial morphology in metabolic diseases. Antioxid. Redox Signal, doi: 10.1089/ars.2012.4779 [Epub ahead of print].
45. Graziewicz, M. A, Day, B. J., and Copeland, W C. (2002). The mitochondrial DNA polymerase as a target of oxidative damage. Nucleic Acids Res. 30,2817-2824.
46. Grigorian, A., Hurford, R., Chao, Y., Patrick, C, and Langford, T. D. (2008). Alterations in the Notch4 pathway in cerebral endothe-lial cells by the HIV aspartyl protease inhibitor, nelfinavir. BMC Neurosci. 9:27. doi: 10.1186/1471-2202-9-27
47. Guaraldi, G., Orlando, G., Zona, S., Menozzi, M., Carli, E, Garlassi, E., et al. (2011). Premature age-related comorbidities among HIV-infected persons compared with the general population. Clin. Infect. Dis. 53, 1120-1126.
48. Hulgan, T., and Gerschenson, M. (2012). HIV and mitochondria: more than just drug toxicity. J. Infect. Dis. 205,1769-1771.
49. Jendrach, M., Pohl, S., Voth, M., Kowald, A., Hammerstein, P., and Bereiter-Hahn, J. (2005). Morpho-dynamic changes of mitochondria during ageing of human endothe-lial cells. Meek Ageing Dev. 126, 813-821.
50. Jiang, B., Hebert, V Y, Li, Y., Mathis, J. M., Alexander, J. S., and Dugas, T. R. (2007). HIV antiretroviral drug combination induces endothelial mitochondrial dysfunction and reactive oxygen species production, but not apoptosis. Toxicol. Appl. Pharmacol. 224,60-71.
51. Khrapko, K. (2011). The timing of mitochondrial DNA mutations in aging. Nat. Genet. 43, 726-727.
52. Klein, R. S. (2011). Trends related to aging and co-occurring disorders in HIV-infected drug users. Subst. Use Misuse 46, 233-244.
53. Lagathu, C, Eustace, B., Prot, M., Frantz, D., Gu, Y, Bastard, J. P., et al. (2007). Some HIV antiretrovi-rals increase oxidative stress and alter chemokine, cytokine or adiponectin production in human adipocytes and macrophages. Antivir. Ther. 12, 489-500.
54. Lee, H. C, and Wei, Y H. (2005). Mitochondrial biogenesis and mitochondrial DNA maintenance of mammalian cells under oxidative stress. Int. J. Biochem. Cell Biol. 37,822-834.
55. Lee, H. C, and Wei, Y H. (2012). Mitochondria and aging. Adv. Exp. Med. Biol. 942,311-327.
56. Lefevre, C, Auclair, M., Boccara, E, Bastard, J. P., Capeau, J., Vigouroux, C, et al. (2010). Premature senescence of vascular cells is induced by HIV protease inhibitors: implication of prelamin A and reversion by statin. Arterioscler. Thromb. Vase. Biol. 30, 2611-2620.
57. Lewis, W., and Dalakas, M. C. (1995). Mitochondrial toxicity of antiviral drugs. Nat. Med. 1 1, 417-422.
58. Lewis, W., Day, B. J., and Copeland, W C. (2003). Mitochondrial toxicity of NRTI antiviral drugs: an integrated cellular perspective. Nat. Rev. Drug Discov. 2,812-822.
59. Lewis, W., Gonzalez, B., Chomyn, A., and Papoian, T. (1992). Zidovudine induces molecular, biochemical, and ultrastructural changes in rat skeletal muscle mitochondria. J. Clin. Invest. 89,1354-1360.
60. Lewis, W, Kohler, J. J., Hosseini, S. H., Haase, C. P., Copeland, W C, Bienstock, R. J., et al. (2006). Antiretroviral nucleosides, deoxynu-cleotide carrier and mitochondrial DNA: evidence supporting the DNA pol y hypothesis. AIDS 20, 675-684.
61. Lim, S. E., and Copeland, W. C. (2001). Differential incorporation and removal of antiviral deoxynu-cleotides by human DNA polymerase y. J. Biol. Chem. 276, 23616-23623.
62. Lohse, N., Hansen, A.-B. E., Peder-sen, G., Kronborg, G., Gerstoft, J., S0rensen, H. T.,et al. (2007). Survival of persons with and without HIV infection in Denmark, 1995-2005. Ann. Intern. Med. 146, 87-95.
63. Lucas, G. M., Cheever, L. W., Chaisson, R. E., and Moore, R. D. (2001). Detrimental effects of continued illicit drug use on the treatment of HIV-1 infection. J. Acquit. Immune Defici. Syndr. 27,251-259.
64. Maagaard, A., and Kvale, D. (2009). Long term adverse effects related to nucleoside reverse transcriptase inhibitors: clinical impact of mito-chondrial toxicity. Scand. J. Infect. Dis. 41, 808-817.
65. Mallon, P. W. G., Unemori, P., Sedwell, R., Morey, A., Rafferty, M., Williams, K., et al. (2005). In vivo, nucleoside reverse-transcriptase inhibitors alter expression of both mitochon-drial and lipid metabolism genes in the absence of depletion of mito-chondrial DNA. J. Infect. Dis. 191, 1686-1696.
66. Manda, K. R., Banerjee, A., Banks, W. A., and Ercal, N. (2011). Highly active antiretroviral therapy drug combination induces oxidative stress and mitochondrial dysfunction in immortalized human blood-brain barrier endothelial cells. Free Radic. Biol Med. 50, 801-810.
67. Mandas, A., Iorio, E. L., Congiu, M. G., Balestrieri, C, Mereu, A., Cau, D., et al. (2009). Oxidative imbalance in HIV-1 infected patients treated with antiretroviral therapy. J. Biomed. Biotechnol. 2009, 749575.
68. Markaki, M., and Tavernarakis, N. (2010). Modeling human diseases in Caenorhabditis elegans. Biotechnol J. 5,1261-1276.
69. Martin, J., and Volberding, P. (2010). HIV and premature aging: a field still in its infancy. Ann. Intern. Med. 153, 477-479.
70. Marzolini, C, Back, D., Weber, R., Furrer, H., Cavassini, M., Calmy, A., et al. (2011). Ageing with HIV: medication use and risk for potential drug-drug interactions. J. Antimi-crob. Chemother. 66,2107-2111.
71. May, M. T., and Ingle, S. M. (2011). Life expectancy of HIV-positive adults: a review. Sex. Health 8, 526-533.
72. McLean, A. J., and Le Couteur, D. G. (2004). Aging biology and geriatric clinical pharmacology. Pharmacol. Rev. 56, 163-184.
73. Mondal, D., Pradhan, L, AH, M., and Agrawal, K. C. (2004). HAART drugs induce oxidative stress in human endothelial cells and increase endothelial recruitment of mononu-clear cells: exacerbation by inflammatory cytokines and amelioration by antioxidants. Cardiovasc. Toxicol 4, 287-302.
74. Neustadt, J., and Pieczenik, S. R. (2008). Medication-induced mitochondrial damage and disease. Mol. Nutr. Food Res. 52, 780-788.
75. Onen, N. E, Overton, E. T., Seyfried, W, Stumm, E. R., Snell, M., Mondy, K., et al. (2010). Aging and HIV infection: a comparison between older HIV-infected persons and the general population. HIV Clin. Trials 11, 100-109.
76. Pan-Zhou, X. R., Cui, L., Zhou, X. I., Sommadossi, I. P., and Darley-Usmar, V M. (2000). Differential effects of antiretroviral nucleoside analogs on mitochondrial function in HepG2 cells. Antimicrob. Agents Chemother. 44, 496-503.
77. Papp, E., Gadawski, I., and Cote, H. C. F. (2008). Longitudinal effects of thymidine analogues on mtDNA, mtRNA and multidrug resistance (MDR-1) induction in cultured cells. J. Antimicrob. Chemother. 61, 1048-1052.
78. Park, C. B., and Larsson, N. G. (2011). Mitochondrial DNA mutations in disease and aging. J. Cell Biol. 193, 809-818.
79. Payne, B. A. I., Wilson, I. J., Hateley, C. A., Horvath, R., Santibanez-Koref, M., Samuels, D. C, et al. (2011). Mitochondrial aging is accelerated by anti-retroviral therapy through the clonal expansion of mtDNA mutations. Nat. Genet 43, 806-810.
80. Pezeshkpour, G., Ilia, I., and Dalakas, M. C. (1991). Ultra-structural characteristics and DNA immunocytochemistry in human immunodeficiency virus and zidovudine-associated myopathies. Hum. Pathol. 22, 1281-1288.
81. Reddy, S., and Comai, L. (2012). Lamin A, farnesylation and aging. Exp. Cell Res. 318, 1-7.
82. Richards, J., and McCallister, S. (2008). Maturation inhibitors as new antiretroviral agents. J. HIV Ther. 13, 79-82.
83. Roumier, T., Szabadkai, G., Simoni, A. M., Perfettini, J. L., Paulau, A. L, Castedo, M., et al. (2006). HIV-1 protease inhibitors and cytomegalovirus vMIA induce mitochondrial fragmentation without triggering apop-tosis. Cell Death. Differ. 13, 348-351.
84. Sastre, J., Pallardo, F. V, and Vina, J. (2000). Mitochondrial oxidative stress plays a key role in aging and apoptosis. IUBMB Life 49, 427-435.
85. Schafer, J. J., and Squires, K. E. (2010). Integrase inhibitors: a novel class of antiretroviral agents. Ann. Pharma-cother. 44,145-156.
86. Schapira, A. H. V (2012). Mitochondrial diseases. Lancet 379, 1825-1834.
87. Sharma, S. K. (2010). Zidovudine-induced anaemia in HIV/AIDS. Indian J. Med. Res. 132, 359-361.
88. Shlay, J. C, Bartsch, G., Peng, G., Wang, J., Grunfeld, C, Gibert, C. L, et al. (2007). Long-term body composition and metabolic changes in antiretroviral naive persons randomized to protease inhibitor-, nonnucle-oside reverse transcriptase inhibitor-, or protease inhibitor plus nonnucle-oside reverse transcriptase inhibitor-based strategy. J. Acquir. Immune Defic. Syndr. 44,506-517.
89. Shurtleff, D., and Lawrence, D. (2012). HIV and substance abuse: a commentary. Curr. HIV Res. 10,366-368.
90. Shutt, T. E., and McBride, H. M. (2012). Staying cool in difficult times: mitochondrial dynamics, quality control and the stress response. Biochim. Biophys. Acta 1833,417-424.
91. Skuta, G., Fischer, G. M., Janaky, T., Kele, Z., Szabo, P., Tozser, J., et al. (1999). Molecular mechanism of the short-term cardiotoxicity caused by 2',3'-dideoxycytidine (ddC): modulation of reactive oxygen species levels and ADP-ribosylation reactions. Biochem. Pharmacol. 58,1915-1925.
92. Stankov, M. V, Liicke, T., Das, A. M., Schmidt, R. E., and Behrens, G. M. N. (2010). 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.
93. Strahl, C, and Blackburn, E. H. (1994). The effects of nucleoside analogs on telomerase and telomeres in Tetrahy-mena. Nucleic Acids Res. 22, 893-900.
94. Sulkowski, M. S. (2008). Viral Hepatitis and HIV Coinfection. J. Hepatol. 48, 353-367.
95. ;-fluorothymidine induces DNA damage and apoptosis in human lym-phoblastoid cells. Antimicrob. Agents Chemother. 40,331-335.
96. Sutliff, R. L, Dikalov, S., Weiss, D., Parker, J., Raidel, S., Racine, A. K., et al. (2002). Nucleoside reverse transcriptase inhibitors impair endothelium-dependent relaxation by increasing superoxide. Am. J. Physiol. Heart Circ. Physiol. 283, H2363-H2370.
97. Teixeira, C, Gomes, J. R. B., Gomes, P., Maurel, E, and Barbault, F. (2011). Viral surface glycoproteins, gpl20 and gp41, as potential drug targets against HIV-1: brief overview one quarter of a century past the approval of zidovudine, the first anti-retroviral drug. Fur. J. Med. Chem. 46,979-992.
98. The Antiretroviral Therapy Cohort Collaboration. (2008). Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet 372,293-299.
99. Tilton, J. C, and Doms, R. W (2010). Entry inhibitors in the treatment of HIV-1 infection. Antivir. Res. 85, 91-100.
100. Trifunovic, A., and Larsson, N.-G. (2008). Mitochondrial dysfunctionas a cause of ageing. J. Intern. Med. 263, 167-178.
101. Trifunovic, A., Wredenberg, A., Falken-berg, M., Spelbrink, J. N., Rovio, A. T., Bruder, C. E., et al. (2004). Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417-423.
102. Tsang, W Y., and Lemire, B. D. (2003). The role of mitochondria in the life of the nematode, Caenorhabditis elegans. Biochim. Biophys. Acta 1638, 91-105.
103. Valenti, D, Barile, M., and Passarella, S. (2000). AZT inhibition of the ADP/ATP antiport in isolated rat heart mitochondria. Int. J. Mol. Med. 6, 93-96.
104. 7-deoxythymidine due to stimulation of superoxide anion mitochondrial production. Biochem. Pharmacol. 64, 201-206.
105. Velsor, L. W, Kovacevic, M., Goldstein, M., Leitner, H. M., Lewis, W, and Day, B. J. (2004). Mitochondrial oxidative stress in human hepatoma cells exposed to stavudine. Toxicol. Appl. Pharmacol. 199,10-19.
106. Viengchareun, S., Caron, M., Auclair, M., Kim, M. J., Frachon, P., Capeau, J., et al. (2007). Mitochondrial toxicity of indinavir, stavudine and zidovudine involves multiple cellular targets in white and brown adipocytes. Antivir. Ther. 12,919-929.
107. Vincent, S., Tourniaire, E, El Yazidi, C. M., Compe, E., Manches, O., Plannels, R., et al. (2004). Nelfi-navir induces necrosis of 3T3F44-2A adipocytes by oxidative stress. J. Acquir. Immune Defic. Syndr. 37, 1556-1562.
108. Wallace, D. C, Fan, W., and Procaccio, V (2010). Mitochondrial energetics and therapeutics. Annu. Rev. Pathol. 5, 297-348.
109. Wang, X., Chai, H., Yao, Q., and Chen, C. (2007). Molecular mechanisms of HIV protease inhibitor-induced endothelial dysfunction. J. Acquit. Immune Defic. Syndr. 44, 493-499.
110. White, A. J. (2001). Mitochondrial tox-icity and HIV therapy. Sex. Transm. Infect. 77, 158-173.
111. Worman, H. J., Fong, L. G., Muchir, A., and Young, S. G. (2009). Laminopathies and the long strange trip from basic cell biology to therapy. J. Clin. Invest. 119, 1825-1836.
112. Yasuda, K., Ishii, T., Suda, H., Akatsuka, A., Hartman, P. S., Goto, S., et al. (2006). Age-related changes of mitochondrial structure and function in Caenorhabditis elegans. Mech. Ageing Dev. 127, 763-770.
113. Zeldin, R. K., and Petruschke, R. A. (2004). Pharmacological and therapeutic properties of ritonavir-boosted protease inhibitor therapy in HIV-infected patients. J. Antimicrob. Chemother. 53,4-9.
114. Zhong, D., Lu, X., Conklin, B. S., Lin, P. H., Lumsden, A. B., Yao, Q., et al. (2002). HIV protease inhibitor ritonavir induces cytotoxi-city of human endothelial cells. Arte-rioscler. Thromb. Vase. Biol. 22, 1560-1566.
115. Zubovych, I. O., Straud, S., and Roth, M. G. (2010). Mitochondrial dysfunction confers resistance to multiple drugs in Caenorhabditis elegans. Mol. Biol Cell 21, 956-969.