News and Commentary
Published: 01 April 2005

Apoptosis of HIV-specific CD8+ T cells: an HIV evasion strategy

C Petrovas¹,
Y M Mueller¹ &
P D Katsikis¹

Cell Death & Differentiation volume 12, pages 859–870 (2005)Cite this article

1732 Accesses
23 Citations
Metrics details

The failure of HIV-specific CD8+ T cells to control HIV has suggested a functional defect for these cells in HIV infection. Recently, HIV-specific CD8+ T cells from HIV-infected patients were shown to exhibit reduced levels of Bcl-2 and Bcl-x_L and to be highly prone to CD95/Fas-induced apoptosis. We hypothesize that this apoptosis of HIV-specific CD8+ T cells may affect their maturation and/or impair effector function. In this review, we discuss the apoptotic defect, the intracellular mediators of this proapoptotic state and the potential mechanisms that result in the priming of HIV-specific CD8+ T cells to apoptosis. Thus, HIV may employ a counterattack mechanism in which HIV-specific CD8+ T cells undergo apoptosis upon engagement of CD95L/FasL on apoptosis-resistant HIV-infected cells. Understanding the mechanisms governing the survival of HIV-specific CD8+ T cells is a prerequisite both for therapeutic interventions and vaccines targeting an effective long-lasting immunoprotective cytotoxic T lymphocyte (CTL) response.

Multiple host factors and their interaction with HIV contribute to the complexity of HIV pathogenesis and disease progression. The urgency to understand the biology of HIV infection emerges from the necessity to develop safe and effective treatments and vaccines. Despite the great advances in this field, over the past few years, critical questions concerning the mechanisms employed by HIV to evade the immune system still remain unanswered. HIV can establish a persistent infection characterized by continuous viral replication, ultimately leading to destruction of the immune system.¹ The CTL response is a major effector arm of the immune defense against HIV virus;^{2, 3} however, this response eventually fails to control virus and prevent AIDS progression. Recent data suggest that accelerated apoptosis of CTLs in HIV infection constitute one of the mechanisms HIV employs to escape immune control. Such apoptosis of CTL may constitute an important obstacle in developing effective therapeutics and vaccines. An ideal HIV vaccine should be able to elicit a robust long-lasting immunity, capable of controlling a wide variety of HIV isolates.⁴ Thus, reconstitution and reinforcement of the CTL function against multiple HIV epitopes is a major goal of therapeutic strategies and vaccines against HIV. Understanding and overcoming the apoptotic defect of naturally occurring and vaccine-elicited HIV-specific CD8+ T cells therefore is an important goal in the quest for novel cellular immunity-based therapies, and therapeutic and preventive vaccines.

References

Douek DC et al. (2003) Annu. Rev. Immunol. 21: 265–304
Borrow P et al. (1997) Nat. Med. 3: 205–211
Gandhi RT and Walker BD (2002) Annu. Rev. Med. 53: 149–172
McMichael AJ and Hanke T (2003) Nat. Med. 9: 874–880
McMichael AJ et al. (1983) N. Engl. J. Med. 309: 13–17
Koup RA et al. (1994) J. Virol. 68: 4650–4655
Walker CM et al. (1986) Science 234: 1563–1566
Walker BD et al. (1987) Nature 328: 345–348
Plata F et al. (1987) Nature 328: 348–351
Pantaleo G et al. (1994) Nature 370: 463–467
Ogg GS et al. (1998) Science 279: 2103–2106
Moss PA et al. (1995) Proc. Natl. Acad. Sci. USA 92: 5773–5777
Altman JD et al. (1996) Science 274: 94–96
Wilson JD et al. (1998) J. Exp. Med. 188: 785–790
Borrow P et al. (1994) J. Virol. 68: 6103–6110
Cao Y et al. (1995) N. Engl. J. Med. 332: 201–208
Oxenius A et al. (2004) J. Infect. Dis. 189: 1199–1208
Oxenius A et al. (2004) J. Infect. Dis. 190: 713–721
Barouch DH et al. (2002) Nature 415: 335–339
Schmitz JE et al. (1999) Science 283: 857–860
Jin X et al. (1999) J. Exp. Med. 189: 991–998
Gray CM et al. (1999) J. Immunol. 162: 1780–1788
Kalams SA et al. (1999) J. Virol. 73: 6721–6728
Oxenius A et al. (2002) J. Clin. Immunol. 22: 363–374
Hess C et al. (2004) Lancet 363: 863–866
Estaquier J et al. (1995) J. Exp. Med. 182: 1759–1767
Katsikis PD et al. (1995) J. Exp. Med. 181: 2029–2036
Moretti S et al. (2000) Clin. Exp. Immunol. 122: 364–373
Gougeon ML (2003) Nat. Rev. Immunol. 3: 392–404
Meyaard L et al. (1992) Science 257: 217–219
Gougeon ML et al. (1993) AIDS Res. Hum. Retroviruses 9: 553–563
Estaquier J et al. (1994) Proc. Natl. Acad. Sci. USA 91: 9431–9435
Katsikis PD et al. (1997) J. Exp. Med. 186: 1365–1372
Finkel TH et al. (1995) Nat. Med. 1: 129–134
Herbein G et al. (1998) J. Virol. 72: 660–670
Rosok BI et al. (1998) AIDS Res. Hum. Retroviruses 14: 1635–1643
Muro-Cacho CA, Pantaleo G and Fauci AS (1995) J. Immunol. 154: 5555–5566
Wei X et al. (1995) Nature 373: 117–122
McCune JM (2001) Nature 410: 974–979
Grossman Z et al. (2002) Nat. Med. 8: 319–323
Gloster SE et al. (2004) AIDS 18: 749–755
Ho DD et al. (1995) Nature 373: 123–126
Lenardo MJ et al. (2002) J. Virol. 76: 5082–5093
Rosenberg YJ and Janossy G (1999) Semin. Immunol. 11: 139–154
Wang L et al. (1999) J. Immunol. 162: 268–276
Hazenberg MD et al. (2000) Nat. Immunol. 1: 285–289
Simmons A, Aluvihare V and McMichael A (2001) Immunity 14: 763–777
Yu Q et al. (2003) J. Immunol. 170: 1797–1805
Carbonneil C et al. (2003) AIDS 17: 1731–1740
Banda NK et al. (1992) J. Exp. Med. 176: 1099–1106
Li CJ et al. (1995) Science 268: 429–431
Mueller YM et al. (2003) Int. Immunol. 15: 49–58
Samuelsson A et al. (1997) Virology 238: 180–188
Prati E et al. (1997) AIDS Res. Hum. Retroviruses 13: 1501–1508
Liegler TJ et al. (1998) J. Infect. Dis. 178: 669–679
Grelli S et al. (2003) Ann. NY Acad. Sci. 1010: 560–564
Badley AD et al. (1999) Cell Death Differ. 6: 420–432
Bohler T et al. (1999) AIDS 13: 779–789
Monceaux V et al. (2003) AIDS 17: 1585–1596
de Oliveira Pinto LM et al. (2002) Blood 99: 1666–1675
Mueller YM et al. (2001) Immunity 15: 871–882
Arnoult D et al. (2003) Cell Death Differ. 10: 1240–1252
Xu XN et al. (1997) J. Exp. Med. 186: 7–16
Piazza C et al. (1997) J. Immunol. 158: 1503–1506
Tateyama M et al. (2000) Blood 96: 195–202
Esser MT et al. (2001) J. Virol. 75: 1152–1164
Geleziunas R et al. (2001) Nature 410: 834–838
Badley AD et al. (1996) J. Virol. 70: 199–206
Dockrell DH et al. (1998) J. Clin. Invest. 101: 2394–2405
Xu XN et al. (1999) J. Exp. Med. 189: 1489–1496
Herbein G et al. (1998) Nature 395: 189–194
Raftery MJ et al. (2001) Immunity 15: 997–1009
Appay V et al. (2002) J. Immunol. 168: 3660–3666
Oxenius A et al. (2001) Eur. J. Immunol. 31: 1115–1121
Oxenius A et al. (2000) Proc. Natl. Acad. Sci. USA 97: 3382–3387
Ogg GS et al. (1999) J. Virol. 73: 797–800
Mohri H et al. (1998) Science 279: 1223–1227
Rosenzweig M et al. (1998) Proc. Natl. Acad. Sci. USA 95: 6388–6393
Mohri H et al. (2001) J. Exp. Med. 194: 1277–1287
Hellerstein M et al. (1999) Nat. Med. 5: 83–89
Kovacs JA et al. (2001) J. Exp. Med. 194: 1731–1741
Gougeon ML et al. (1996) J. Immunol. 156: 3509–3520
Zaunders JJ et al. (2003) J. Infect. Dis. 187: 1735–1747
Silvestri G et al. (2003) Immunity 18: 441–452
Cannavo G et al. (2001) Blood 97: 1756–1764
Paiardini M et al. (2004) Immunol. Res. 29: 253–268
Paiardini M et al. (2004) AIDS 18: 393–402
Chun TW et al. (2004) Proc. Natl. Acad. Sci. USA 101: 2464–2469
Brenchley JM et al. (2003) Blood 101: 2711–2720
Singer GG and Abbas AK (1994) Immunity 1: 365–371
Cossarizza A et al. (2000) AIDS 14: 345–355
Moskophidis D, Laine E and Zinkernagel RM (1993) Eur. J. Immunol. 23: 3306–3311
Moskophidis D et al. (1993) Nature 362: 758–761
Zhou S et al. (2002) J. Virol. 76: 829–840
Zhou S et al. (2004) J. Virol. 78: 3578–3600
Pantaleo G et al. (1991) Proc. Natl. Acad. Sci. USA 88: 9838–9842
Masopust D et al. (2001) Science 291: 2413–2417
Wang XZ et al. (2003) Immunity 18: 631–642
Douek DC et al. (2002) Nature 417: 95–98
Trimble LA et al. (2000) Blood 96: 1021–1029
Geertsma MF et al. (1999) J. Infect. Dis. 180: 649–658
Lloyd TE et al. (1997) J. Immunol. 158: 1551–1558
Trimble LA and Lieberman J (1998) Blood 91: 585–594
Gamberg J et al. (2004) Immunol. Cell Biol. 82: 38–46
Topp MS et al. (2003) J. Exp. Med. 198: 947–955
Trimble LA et al. (2000) J. Virol. 74: 7320–7330
Leist TP et al. (1987) J. Immunol. 138: 2278–2281
Matloubian M et al. (1994) J. Virol. 68: 8056–8063
von Herrath MG et al. (1996) J. Virol. 70: 1072–1079
Janssen EM et al. (2003) Nature 421: 852–856
Schoenberger SP et al. (1998) Nature 393: 480–483
Vella AT et al. (1998) Proc. Natl. Acad. Sci. USA 95: 3810–3815
Klein MR et al. (1995) J. Exp. Med. 181: 1365–1372
Rosenberg ES et al. (1997) Science 278: 1447–1450
Iyasere C et al. (2003) J. Virol. 77: 10900–10909
Kalams SA et al. (1999) J. Virol. 73: 6715–6720
Ostrowski MA et al. (2000) J. Immunol. 165: 6133–6141
Gea-Banacloche JC et al. (2000) J. Immunol. 165: 1082–1092
Papagno L et al. (2002) Clin. Exp. Immunol. 130: 509–517
Betts MR et al. (2001) J. Virol. 75: 11983–11991
Kalams SA and Walker BD (1998) J. Exp. Med. 188: 2199–2204
Bevan MJ (2004) Nat. Rev. Immunol. 4: 595–602
Selliah N and Finkel TH (2001) Cell. Death Differ. 8: 127–136
Vlahakis SR et al. (2001) J. Clin. Invest. 107: 207–215
Algeciras-Schimnich A et al. (2002) AIDS 16: 1467–1478
Decrion AZ et al. (2004) J. Gen. Virol. 85: 1471–1478
Penn ML et al. (1999) Proc. Natl. Acad. Sci. USA 96: 663–668
Katsikis PD et al. (1997) Int. Immunol. 9: 835–841
Ferri KF et al. (2000) Ann. NY Acad. Sci. 926: 149–164
Jacotot E et al. (2001) J. Exp. Med. 193: 509–519
Imami N et al. (2002) J. Virol. 76: 9011–9023
Paiardini M et al. (2001) J. Virol. 75: 10843–10855
Adachi Y et al. (1996) J. Immunol. 157: 4184–4193
Estaquier J et al. (1996) Blood 87: 4959–4966
Naora H and Gougeon ML (1999) Cell Death Differ. 6: 1002–1011
Mueller YM et al. (2003) Blood 101: 1024–1029
Chehimi J et al. (1997) J. Immunol. 158: 5978–5987
Clerici M and Shearer GM (1994) Immunol. Today 15: 575–581
Ledru E et al. (1998) J. Immunol. 160: 3194–3206
Pericle F et al. (1998) J. Immunol. 160: 28–31
Kryworuchko M et al. (2004) AIDS 18: 421–426
MacPherson PA et al. (2001) J. Acquir. Immune Defic. Syndr. 28: 454–457
Marchetti G et al. (2004) Antivir. Ther. 9: 447–452
Westendorp MO et al. (1995) Nature 375: 497–500
Quaranta MG et al. (2004) FASEB J. 18: 1459–1461
Ahr B et al. (2004) Retrovirology 1: 1–12
Krammer PH (2000) Nature 407: 789–795
Peter ME and Krammer PH (2003) Cell Death Differ. 10: 26–35
Cory S and Adams JM (2002) Nat. Rev. Cancer 2: 647–656
Scaffidi C et al. (1998) EMBO J. 17: 1675–1687
Petrovas C et al. (2004) J. Immunol. 172: 4444–4453
Chao DT et al. (1995) J. Exp. Med. 182: 821–828
Thompson CB (1995) Science 267: 1456–1462
Boudet F, Lecoeur H and Gougeon ML (1996) J. Immunol. 156: 2282–2293
Blair PJ et al. (1997) J. Clin. Immunol. 17: 234–246
Hildeman DA et al. (2003) Proc. Natl. Acad. Sci. USA 100: 15035–15040
Macho A et al. (1995) Blood 86: 2481–2487
Papagno L et al. (2004) PLoS Biol. 2: 173–185
Borner C (1996) J. Biol. Chem. 271: 12695–12698
Linette GP et al. (1996) Proc. Natl. Acad. Sci. USA 93: 9545–9552
Bonnefoy-Berard N et al. (2004) Biochim. Biophys. Acta 1644: 159–168
Groux H et al. (1992) J. Exp. Med. 175: 331–340
Cossarizza A et al. (1997) AIDS 11: 19–26
Badley AD et al. (2003) Trends Pharmacol. Sci. 24: 298–305
Haeffner A et al. (1999) Eur. J. Immunol. 29: 334–344
Sun XM et al. (2002) J. Biol. Chem. 277: 11345–11351
Petit F et al. (2003) Biochimie 85: 795–811
Rippo MR et al. (2000) FASEB J. 14: 2047–2054
De Simone C et al. (1996) AIDS 10: 675–676
De Simone C et al. (1996) Immunol. Today 17: 48
Luo X et al. (1998) Cell 94: 481–490
Fackler OT and Baur AS (2002) Immunity 16: 493–497
Goulder PJ and Watkins DI (2004) Nat. Rev. Immunol. 4: 630–640
Thomsen AR et al. (2003) Immunol. Lett. 85: 119–127
Hamann D et al. (1997) J. Exp. Med. 186: 1407–1418
Sallusto F et al. (1999) Nature 401: 708–712
Tussey L et al. (2000) Eur. J. Immunol. 30: 1823–1829
Baars PA et al. (2000) J. Immunol. 165: 1910–1917
Franco A et al. (2000) Nat. Immunol. 1: 145–150
Manjunath N et al. (2001) J. Clin. Invest. 108: 871–878
Champagne P et al. (2001) Nature 410: 106–111
Chen G et al. (2001) Blood 98: 156–164
Kuroda MJ et al. (1999) J. Virol. 73: 1573–1579
Kuroda MJ et al. (2000) Blood 96: 1474–1479
Harty JT et al. (2000) Annu. Rev. Immunol. 18: 275–308
Kagi D et al. (1996) Annu. Rev. Immunol. 14: 207–232
Betts MR et al. (2000) J. Virol. 74: 9144–9151
Valitutti S et al. (1996) J. Exp. Med. 183: 1917–1921
Betts MR et al. (2004) J. Immunol. 172: 6407–6417
Koup RA et al. (1989) Blood 73: 1909–1914
Riviere Y et al. (1989) J. Virol. 63: 2270–2277
Lichterfeld M et al. (2004) Blood 104: 487–494
Shankar P et al. (2000) Blood 96: 3094–3101
Appay V et al. (2000) J. Exp. Med. 192: 63–75
Lieberman J et al. (2002) Curr. Opin. Immunol. 14: 478–486
Tanner JE and Alfieri C (1999) Blood 94: 3439–3447
Trabattoni D et al. (2004) AIDS 18: 859–869
Shacklett BL et al. (2004) J. Immunol. 173: 641–648
Stevceva L et al. (2004) Virology 319: 190–200
Goulder PJ et al. (2000) J. Exp. Med. 192: 1819–1832
Islam SA et al. (2001) J. Virol. 75: 4907–4911
Ullum H et al. (1997) AIDS Res. Hum. Retroviruses 13: 1039–1046
Bailer RT et al. (1999) J. Immunol. 162: 7534–7542
Benito JM et al. (2003) J. Acquir. Immune Defic. Syndr. 34: 255–266
Ince MN et al. (2004) Immunology 112: 531–542
Wagner L et al. (1998) Nature 391: 908–911
Heintel T et al. (2002) AIDS 16: 1497–1501
Hoffenbach A et al. (1989) J. Immunol. 142: 452–462
Koup RA et al. (1991) J. Exp. Med. 174: 1593–1600
Carmichael A et al. (1993) J. Exp. Med. 177: 249–256
Murali-Krishna K et al. (1998) Immunity 8: 177–187
Tan LC et al. (1999) J. Immunol. 162: 1827–1835
McMichael AJ and Phillips RE (1997) Annu. Rev. Immunol. 15: 271–296
O’Connor D et al. (2001) Immunol. Rev. 183: 115–126
Grakoui A et al. (2003) Science 302: 659–662

Download references

Acknowledgements

This work was supported in part by National Institutes of Health Grants R01 AI46719 and R01 AI52005 to PDK.

Author information

Authors and Affiliations

Department of Microbiology and Immunology, and Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA, 19129, USA
C Petrovas, Y M Mueller & P D Katsikis

Authors

C Petrovas
View author publications
Search author on:PubMed Google Scholar
Y M Mueller
View author publications
Search author on:PubMed Google Scholar
P D Katsikis
View author publications
Search author on:PubMed Google Scholar

Corresponding author

Correspondence to P D Katsikis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Petrovas, C., Mueller, Y. & Katsikis, P. Apoptosis of HIV-specific CD8+ T cells: an HIV evasion strategy. Cell Death Differ 12 (Suppl 1), 859–870 (2005). https://doi.org/10.1038/sj.cdd.4401595

Download citation

Published: 01 April 2005
Issue date: 01 August 2005
DOI: https://doi.org/10.1038/sj.cdd.4401595

This article is cited by

Actin integrity is indispensable for CD95/Fas-induced apoptosis of HIV-specific CD8+ T cells
- Constantinos Petrovas
- Yvonne M. Mueller
- Peter D. Katsikis
Apoptosis (2007)

Apoptosis of HIV-specific CD8+ T cells: an HIV evasion strategy

Log in or create a free account to read this content

References

Acknowledgements

Author information

Authors and Affiliations

Corresponding author

Rights and permissions

About this article

Cite this article

This article is cited by

Actin integrity is indispensable for CD95/Fas-induced apoptosis of HIV-specific CD8+ T cells

Search

Quick links

Log in or create a free account to read this content

References

Acknowledgements

Author information

Authors and Affiliations

Corresponding author

Rights and permissions

About this article

Cite this article

Share this article

This article is cited by

Actin integrity is indispensable for CD95/Fas-induced apoptosis of HIV-specific CD8+ T cells

Search

Quick links