, Volume 12, Issue 5, pp 969–977

HIV protease inhibitors modulate apoptosis signaling in vitro and in vivo

  • Stacey R. Vlahakis
  • Steffany A. L. Bennett
  • Shawn N. Whitehead
  • Andrew D. Badley


HIV protease inhibitors are an integral part of effective anti-HIV therapy. The drugs block HIV protease, prevent proper packaging of HIV virions, and decrease the HIV viral burden in the peripheral blood of infected individuals. In addition to direct anti-viral effects, the HIV protease inhibitors also modulate apoptosis. A growing body of work demonstrates the anti-apoptotic effects of HIV protease inhibitors on CD4+ and CD8+ T cells during HIV infection. The mechanism of this apoptosis inhibition is supported by several proposed hypotheses for how they alter the fate of the cell, including preventing adenine nucleotide translocator pore function, which consequently prevents loss of mitochondrial transmembrane potential. More recently, the anti-apoptotic effects of the HIV protease inhibitors have been tested in non-HIV, non-immune cell, whereby protease inhibitors prevent apoptosis, and disease in animal models of sepsis, hepatitis, pancreatitis and stroke. Interestingly, when HIV protease inhibitors are used at supra-therapeutic concentrations, they exert pro-apoptotic effects. This has been demonstrated in a number of tumor models. Although it is unclear how HIV protease inhibitors can induce apoptosis at increased concentrations, future research will define the targets of the immunomodulation and reveal the full clinical potential of this intriguing class of drugs.


Apoptosis HIV protease inhibitors Neurons Mitochondria 


  1. 1.
    Collier AC, Coombs RW, Schoenfeld DA et al (1996) Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine: AIDS Clinical Trials Group. N Engl J Med 334(16):1011–1017PubMedCrossRefGoogle Scholar
  2. 2.
    Kravcik S, Magill A, Sanghvi B et al (2001) Comparative CD4 T-cell responses of reverse transcriptase inhibitor therapy with or without nelfinavir matched for viral exposure. HIV Clin Trials 2(2):160–170PubMedCrossRefGoogle Scholar
  3. 3.
    Deeks SG, Grant RM. (1999) Sustained CD4 responses after virological failure of protease inhibitor-containing therapy. Antivir Ther 4(Suppl 3):7–11PubMedGoogle Scholar
  4. 4.
    Albrecht MA, Bosch RJ, Hammer SM et al (2001) Nelfinavir, efavirenz, or both after the failure of nucleoside treatment of HIV infection. N Engl J Med 345(6):398–407PubMedCrossRefGoogle Scholar
  5. 5.
    Staszewski S, Morales-Ramirez J, Tashima KT et al (1999) 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(25):1865–1873PubMedCrossRefGoogle Scholar
  6. 6.
    Owen C, Kazim F, Badley AD (2004) Effect on CD4 T-cell count of replacing protease inhibitors in patients with successful HIV suppression: a meta-analysis. Aids 18(4):693–695PubMedCrossRefGoogle Scholar
  7. 7.
    Arribas JR, Pulido F, Delgado R et al (2005) Lopinavir/ritonavir as single-drug therapy for maintenance of HIV-1 viral suppression: 48-week results of a randomized, controlled, open-label, proof-of-concept pilot clinical trial (OK Study). J Acquir Immune Defic Syndr 40(3):280–287PubMedCrossRefGoogle Scholar
  8. 8.
    Fethi T, Asma J, Amine SM et al (2005) Effects on immunological and virological outcome of patients using one protease inhibitor or one non-nucleoside reverse transcriptase inhibitor in a triple antiretroviral therapy: normal clinical practice versus clinical trial findings. Curr HIV Res 3(3):271–276PubMedCrossRefGoogle Scholar
  9. 9.
    Badley AD, Dockrell DH, Algeciras A et al (1998) in vivo analysis of Fas/FasL interactions in HIV-infected patients. J Clin Invest 102(1):79–87PubMedGoogle Scholar
  10. 10.
    Landay AL, Spritzler J, Kessler H et al (2003) Immune reconstitution is comparable in antiretroviral-naive subjects after 1 year of successful therapy with a nucleoside reverse-transcriptase inhibitor- or protease inhibitor-containing antiretroviral regimen. J Infect Dis 188(10):1444–1454PubMedCrossRefGoogle Scholar
  11. 11.
    Badley AD, Parato K, Cameron DW et al (1999) Dynamic correlation of apoptosis and immune activation during treatment of HIV infection. Cell Death Differ 6(5):420–432PubMedCrossRefGoogle Scholar
  12. 12.
    Phenix BN, Angel JB, Mandy F et al (2000) Decreased HIV-associated T cell apoptosis by HIV protease inhibitors. AIDS Res Hum Retroviruses 16(6):559–567PubMedCrossRefGoogle Scholar
  13. 13.
    Sloand EM, Maciejewski J, Kumar P, Kim S, Chaudhuri A, Young N. (2000) Protease inhibitors stimulate hematopoiesis and decrease apoptosis and ICE expression in CD34(+) cells. Blood 96(8):2735–2739PubMedGoogle Scholar
  14. 14.
    Estaquier J, Lelievre JD, Petit F et al (2002) Effects of antiretroviral drugs on human immunodeficiency virus type 1-induced CD4(+) T-cell death. J Virol 76(12):5966–5973PubMedCrossRefGoogle Scholar
  15. 15.
    Wolf T, Findhammer S, Nolte B, Helm EB, Brodt HR. (2003) Inhibition of TNF-alpha mediated cell death by HIV-1 specific protease inhibitors. Eur J Med Res 8(1):17–24PubMedGoogle Scholar
  16. 16.
    Matarrese P, Tinari A, Gambardella L et al (2005) HIV protease inhibitors prevent mitochondrial hyperpolarization and redox imbalance and decrease endogenous uncoupler protein-2 expression in gp 120-activated human T lymphocytes. Antivir Ther 10(Suppl 2):M29–M45PubMedGoogle Scholar
  17. 17.
    Phenix BN, Lum JJ, Nie Z, Sanchez-Dardon J, Badley AD. (2001) Antiapoptotic mechanism of HIV protease inhibitors: preventing mitochondrial transmembrane potential loss. Blood 98(4):1078–1085PubMedCrossRefGoogle Scholar
  18. 18.
    Ghibelli L, Mengoni F, Lichtner M et al (2003) Anti-apoptotic effect of HIV protease inhibitors via direct inhibition of calpain. Biochem Pharmacol 66(8):1505–1512PubMedCrossRefGoogle Scholar
  19. 19.
    Chavan S, Kodoth S, Pahwa R, Pahwa S (2001) The HIV protease inhibitor Indinavir inhibits cell-cycle progression in vitro in lymphocytes of HIV-infected and uninfected individuals. Blood 98(2):383–389PubMedCrossRefGoogle Scholar
  20. 20.
    Spinedi A, Oliverio S, Di Sano F, Piacentini M (1998) Calpain involvement in calphostin C-induced apoptosis. Biochem Pharmacol 56(11):1489–1492PubMedCrossRefGoogle Scholar
  21. 21.
    Wan W, DePetrillo PB (2002) Ritonavir inhibition of calcium-activated neutral proteases. Biochem Pharmacol 63(8):1481–1484PubMedCrossRefGoogle Scholar
  22. 22.
    Cuerrier D, Nie Z, Badley AD, Davies PL (2005) Ritonavir does not inhibit calpain in vitro. Biochem Biophys Res Commun 327(1):208–211PubMedCrossRefGoogle Scholar
  23. 23.
    Sloand EM, Kumar PN, Kim S, Chaudhuri A, Weichold FF, Young NS (1999) Human immunodeficiency virus type 1 protease inhibitor modulates activation of peripheral blood CD4(+) T cells and decreases their susceptibility to apoptosis in vitro and in vivo. Blood 94(3):1021–1027PubMedGoogle Scholar
  24. 24.
    Lu W, Andrieu JM (2000) HIV protease inhibitors restore impaired T-cell proliferative response in vivo and in vitro: a viral-suppression-independent mechanism. Blood 96(1):250– 258PubMedGoogle Scholar
  25. 25.
    Isgro A, Aiuti A, Mezzaroma I et al (2005) HIV type 1 protease inhibitors enhance bone marrow progenitor cell activity in normal subjects and in HIV type 1-infected patients. AIDS Res Hum Retroviruses 21(1):51–57PubMedCrossRefGoogle Scholar
  26. 26.
    Matarrese P, Gambardella L, Cassone A, Vella S, Cauda R, Malorni W (2003) Mitochondrial membrane hyperpolarization hijacks activated T lymphocytes toward the apoptotic-prone phenotype: homeostatic mechanisms of HIV protease inhibitors. J Immunol 170(12):6006–6015PubMedGoogle Scholar
  27. 27.
    Weichold FF, Bryant JL, Pati S, Barabitskaya O, Gallo RC, Reitz Jr MS (1999) HIV-1 protease inhibitor ritonavir modulates susceptibility to apoptosis of uninfected T cells. J Hum Virol 2(5):261–269PubMedGoogle Scholar
  28. 28.
    Badley AD, Roumier T, Lum JJ, Kroemer G (2003) Mitochondrion-mediated apoptosis in HIV-1 infection. Trends Pharmacol Sci 24(6):298–305PubMedCrossRefGoogle Scholar
  29. 29.
    Garg H, Blumenthal R (2006) HIV gp41-induced apoptosis is mediated by caspase-3-dependent mitochondrial depolarization, which is inhibited by HIV protease inhibitor nelfinavir. J Leukoc Biol 79(2):351–362PubMedCrossRefGoogle Scholar
  30. 30.
    Miro O, Villarroya J, Garrabou G et al (2005) in vivo effects of highly active antiretroviral therapies containing the protease inhibitor nelfinavir on mitochondrially driven apoptosis. Antivir Ther 10(8):945–951PubMedGoogle Scholar
  31. 31.
    Weaver JG, Tarze A, Moffat TC et al (2005) Inhibition of adenine nucleotide translocator pore function and protection against apoptosis in vivo by an HIV protease inhibitor. J Clin Invest 115(7):1828–1838PubMedCrossRefGoogle Scholar
  32. 32.
    Ayala A, Herdon CD, Lehman DL, Ayala CA, Chaudry IH (1996) Differential induction of apoptosis in lymphoid tissues during sepsis: variation in onset, frequency, and the nature of the mediators. Blood 87(10):4261–4275PubMedGoogle Scholar
  33. 33.
    Hotchkiss RS, Swanson PE, Cobb JP, Jacobson A, Buchman TG, Karl IE (1997) Apoptosis in lymphoid and parenchymal cells during sepsis: findings in normal and T- and B-cell-deficient mice. Crit Care Med 25(8):1298–1307PubMedCrossRefGoogle Scholar
  34. 34.
    Husain KD, Coopersmith CM (2003) Role of intestinal epithelial apoptosis in survival. Curr Opin Crit Care 9(2):159–163PubMedCrossRefGoogle Scholar
  35. 35.
    Coopersmith CM, Chang KC, Swanson PE et al (2002) Overexpression of Bcl-2 in the intestinal epithelium improves survival in septic mice. Crit Care Med 30(1):195–201PubMedCrossRefGoogle Scholar
  36. 36.
    Weaver JG, Rouse MS, Steckelberg JM, Badley AD (2004) Improved survival in experimental sepsis with an orally administered inhibitor of apoptosis. Faseb J 18(11):1185–1191PubMedCrossRefGoogle Scholar
  37. 37.
    Ly JV, Zavala JA, Donnan GA (2006) Neuroprotection and thrombolysis: combination therapy in acute ischaemic stroke. Expert Opin Pharmacother 7(12):1571–1581PubMedCrossRefGoogle Scholar
  38. 38.
    Lee JM, Zipfel GJ, Choi DW (1999) The changing landscape of ischaemic brain injury mechanisms. Nature 399(6738 Suppl):A7–A14PubMedGoogle Scholar
  39. 39.
    Reed JC (2001) Apoptosis-regulating proteins as targets for drug discovery. Trends Mol Med 7(7):314–319PubMedCrossRefGoogle Scholar
  40. 40.
    Lo EH, Moskowitz MA, Jacobs TP (2005) Exciting, radical, suicidal: how brain cells die after stroke. Stroke 36(2):189–192PubMedCrossRefGoogle Scholar
  41. 41.
    Rosenfeldt V, Valerius NH, Paerregaard A (2000) Regression of HIV-associated progressive encephalopathy of childhood during HAART. Scand J Infect Dis 32(5):571–574PubMedCrossRefGoogle Scholar
  42. 42.
    MacGowan DJ, Scelsa SN, Waldron M (2001) An ALS-like syndrome with new HIV infection and complete response to antiretroviral therapy. Neurology 57(6):1094–1097PubMedGoogle Scholar
  43. 43.
    Lopez-Neblina F, Toledo AH, Toledo-Pereyra LH (2005) Molecular biology of apoptosis in ischemia and reperfusion. J Invest Surg 18(6):335–350PubMedCrossRefGoogle Scholar
  44. 44.
    MacDonald JF, Xiong ZG, Jackson MF (2006) Paradox of Ca2+ signaling, cell death and stroke. Trends Neurosci 29(2):75–81PubMedCrossRefGoogle Scholar
  45. 45.
    Wan W, DePetrillo PB (2002) Ritonavir protects hippocampal neurons against oxidative stress-induced apoptosis. Neurotoxicology 23(3):301–306PubMedCrossRefGoogle Scholar
  46. 46.
    Ferrer I, Planas AM (2003) Signaling of cell death and cell survival following focal cerebral ischemia: life and death struggle in the penumbra. J Neuropathol Exp Neurol 62(4):329–339PubMedGoogle Scholar
  47. 47.
    Zheng Z, Zhao H, Steinberg GK, Yenari MA (2003) Cellular and molecular events underlying ischemia-induced neuronal apoptosis. Drug News Perspect 16(8):497–503PubMedCrossRefGoogle Scholar
  48. 48.
    Phenix BN, Cooper C, Owen C, Badley AD (2002) Modulation of apoptosis by HIV protease inhibitors. Apoptosis 7(4):295–312PubMedCrossRefGoogle Scholar
  49. 49.
    Pajonk F, Himmelsbach J, Riess K, Sommer A, McBride WH (2002) The human immunodeficiency virus (HIV)-1 protease inhibitor saquinavir inhibits proteasome function and causes apoptosis and radiosensitization in non-HIV-associated human cancer cells. Cancer Res 62(18):5230–5235PubMedGoogle Scholar
  50. 50.
    Zhong DS, Lu XH, Conklin BS et al (2002) HIV protease inhibitor ritonavir induces cytotoxicity of human endothelial cells. Arterioscler Thromb Vasc Biol 22(10):1560–1566PubMedCrossRefGoogle Scholar
  51. 51.
    Bode H, Lenzner L, Kraemer OH et al (2005) The HIV protease inhibitors saquinavir, ritonavir, and nelfinavir induce apoptosis and decrease barrier function in human intestinal epithelial cells. Antivir Ther 10(5):645–655PubMedGoogle Scholar
  52. 52.
    Penzak SR, Chuck SK (2002) Management of protease inhibitor-associated hyperlipidemia. Am J Cardiovasc Drugs 2(2):91–106PubMedCrossRefGoogle Scholar
  53. 53.
    Lai S, Lai H, Celentano DD et al (2003) Factors associated with accelerated atherosclerosis in HIV-1-infected persons treated with protease inhibitors. AIDS Patient Care STDS 17(5):211–219PubMedCrossRefGoogle Scholar
  54. 54.
    Cohen CJ (2005) Ritonavir-boosted protease inhibitors, Part 2: cardiac implications of lipid alterations. AIDS Read 15(10):528–532PubMedGoogle Scholar
  55. 55.
    Graham DB, Bell MP, Huntoon CJ et al (2005) Increased thymic output in HIV-negative patients after antiretroviral therapy. Aids 19(14):1467–1472PubMedCrossRefGoogle Scholar
  56. 56.
    Gaedicke S, Firat-Geier E, Constantiniu O et al (2002) Antitumor effect of the human immunodeficiency virus protease inhibitor ritonavir: induction of tumor-cell apoptosis associated with perturbation of proteasomal proteolysis. Cancer Res 62(23):6901–6908PubMedGoogle Scholar
  57. 57.
    Dewan MZ, Uchihara JN, Terashima K et al (2006) Efficient intervention of growth and infiltration of primary adult T-cell leukemia cells by an HIV protease inhibitor, ritonavir. Blood 107(2):716–724PubMedCrossRefGoogle Scholar
  58. 58.
    Ikezoe T, Saito T, Bandobashi K, Yang Y, Koeffler HP, Taguchi H (2004) HIV-1 protease inhibitor induces growth arrest and apoptosis of human multiple myeloma cells via inactivation of signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1/2. Mol Cancer Ther 3(4):473–479PubMedGoogle Scholar
  59. 59.
    Andre P, Groettrup M, Klenerman P et al (1998) An inhibitor of HIV-1 protease modulates proteasome activity, antigen presentation, and T cell responses. Proc Natl Acad Sci USA 95(22):13120–13124PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media, LLC 2007

Authors and Affiliations

  • Stacey R. Vlahakis
    • 1
  • Steffany A. L. Bennett
    • 2
  • Shawn N. Whitehead
    • 2
  • Andrew D. Badley
    • 1
  1. 1.Division Infectious DiseaseMayo Clinic College of MedicineRochester
  2. 2.Neural Regeneration Laboratory, Department of Biochemistry, Microbiology and ImmunologyUniversity of OttawaOttawaCanada

Personalised recommendations