Skip to main content

Advertisement

SpringerLink
Log in

New insights on the role of apoptosis and autophagy in HIV pathogenesis

  • Cell Death and Disease
  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

Viruses manipulate host cells to ensure their own survival and, at late stages of the viral life cycle, they kill the infected target cell to ensure their propagation. In addition, some viruses induce a bystander killing, a viral strategy to escape from the host's innate and cognate defense systems. In HIV-infection, the disabling of the immune system is initially due to the preferential depletion by apoptosis of virus-specific CD4+ T cells in lymphoid tissues, followed by the destruction of non-infected bystander cells. Both the extrinsic and the intrinsic pathways are activated, and this is the consequence of systemic immune activation. This review presents recent developments showing that the gastrointestinal tract is the major reservoir of infected cells and the site of rapid and profound loss of CD4 T cells, and that microbial translocation from the gastrointestinal tract is the cause of immune activation. Furthermore, apoptosis mechanisms involved in HIV-induced neuropathological disorders are discussed, including the role of syncytia that involve the sequential activation of ATM, p38MAPK and p53. Finally, HIV-associated dementia (HAD) was recently found in monkey models to be linked to inhibition of autophagy in neurons, suggesting that homeostasis of autophagy is a reliable security factor for neurons, and challenging the development of new therapeutics aimed at boosting neuronal autophagy to prevent HAD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Gougeon M-L (2005) To kill or be killed: how HIV exhausts the immune system. Cell Death Differ 12:845–854. doi:10.1038/sj.cdd.4401616

    Article  PubMed  CAS  Google Scholar 

  2. Espert L, Denizot M, Grimaldi M, Robert-Hebmann V, Gay B, Varbanov M, Codogno P, Biard-Piechaczyk M (2006) Autophagy is involved in T cell death after binding of HIV-1 envelope proteins to CXCR4. J Clin Invest 116:2161–2172. doi:10.1172/JCI26185

    Article  PubMed  CAS  Google Scholar 

  3. Spector SA, Zhou D (2008) Autophagy: an overlooked mechanism of HIV-1 pathogenesis and neuroAIDS? Autophagy 4:704–706

    PubMed  CAS  Google Scholar 

  4. Douek DC, Brenchley JM, Betts MR et al (2002) HIV preferentially infects HIV-specific CD4+ T cells. Nature 417:95–98. doi:10.1038/417095a

    Article  PubMed  CAS  Google Scholar 

  5. Haase AT (2005) Peril at mucosal front lines for HIV and SIV and their hosts. Nat Rev Immunol 5:783–792

    PubMed  CAS  Google Scholar 

  6. Amendola A, Gougeon M-L, Poccia F, Bondurand A, Fesus L, Piacentini M (1996) Induction of “tissue” transglutaminase in HIV pathogenesis: evidence for high rate of apoptosis of CD4+ T lymphocytes and accessory cells in lymphoid tissues. Proc Natl Acad Sci USA 93:11057–11062. doi:10.1073/pnas.93.20.11057

    Article  PubMed  CAS  Google Scholar 

  7. Muro-Cacho CA, Pantaleo G, Fauci AS (1995) Analysis of apoptosis in lymph nodes of HIV-infected persons. Intensity of apoptosis correlates with the general state of activation of the lymphoid tissue and not with stage of disease or viral burden. J Immunol 154:5555–5566

    PubMed  CAS  Google Scholar 

  8. Brenchley JM, Schacker TW, Ruff LE et al (2004) CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med 200:749–759. doi:10.1084/jem.20040874

    Article  PubMed  CAS  Google Scholar 

  9. Douek DC (2007) HIV disease progression: immune activation, microbes and a leaky gut. Top HIV Med 15:114–117

    PubMed  Google Scholar 

  10. Li Q, Duan L, Estes JD, Ma ZM et al (2005) Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells. Nature 434:1148–1152

    PubMed  CAS  Google Scholar 

  11. Gougeon M-L (1995) Chronic activation of the immune system in HIV infection: contribution to T cell apoptosis and V beta selective T cell anergy. Curr Top Microbiol Immunol 200:177–193

    PubMed  CAS  Google Scholar 

  12. Giorgi JV, Hultin LE, McKeating JA et al (1999) Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. J Infect Dis 179:859–870. doi:10.1086/314660

    Article  PubMed  CAS  Google Scholar 

  13. Gougeon M-L, Lecoeur H, Boudet F, Ledru E, Marzabal S, Boullier S, Roué R, Nagata S, Heeney J (1997) Lack of chronic immune activation in HIV-infected chimpanzees correlates with the resistance of T cells to Fas/Apo-1 (CD95)-induced apoptosis and preservation of a T helper 1 phenotype. J Immunol 158:2964–2976

    PubMed  CAS  Google Scholar 

  14. Silvestri G, Paiardini M, Pandrea I et al (2007) Understanding the benign nature of SIV infection in natural hosts. J Clin Invest 117:3148–3154. doi:10.1172/JCI33034

    Article  PubMed  CAS  Google Scholar 

  15. Lane HC, Masur H, Edgar LC et al (1983) Abnormalities of B-cell activation and immunoregulation in patients with the acquired immunodeficiency syndrome. N Engl J Med 309:453–458

    PubMed  CAS  Google Scholar 

  16. Gougeon M-L, Lecoeur H, Dulioust A, Enouf MG, Crouvoiser M, Goujard C, Debord T, Montagnier L (1996) Programmed cell death in peripheral lymphocytes from HIV-infected persons: increased susceptibility to apoptosis of CD4 and CD8 T cells correlates with lymphocyte activation and with disease progression. J Immunol 156:3509–3520

    PubMed  CAS  Google Scholar 

  17. Hazenberg MD, Stuart JW, Otto SA et al (2000) T-cell division in human immunodeficiency virus (HIV)-1 infection is mainly due to immune activation: a longitudinal analysis in patients before and during highly active antiretroviral therapy (HAART). Blood 95:249–255

    PubMed  CAS  Google Scholar 

  18. Ledru E, Lecoeur H, Garcia S, Debord T, Gougeon M-L (1998) Differential susceptibility to activation-induced apoptosis among peripheral Th1 subsets: correlation with Bcl-2 expression and consequences for AIDS pathogenesis. J Immunol 160:3194–3206

    PubMed  CAS  Google Scholar 

  19. de Oliveira Pinto LM, Garcia S, Lecoeur H, Rapp C, Gougeon M-L (2002) Increased sensitivity of T lymphocytes to tumor necrosis factor receptor 1 (TNFR1)- and TNFR2-mediated apoptosis in HIV infection: relation to expression of Bcl-2 and active caspase-8 and caspase-3. Blood 99:1666–1675. doi:10.1182/blood.V99.5.1666

    Article  PubMed  Google Scholar 

  20. Moir S, Malaspina A, Pickeral OK et al (2004) Decreased survival of B cells of HIV-viremic patients mediated by altered expression of receptors of the TNF superfamily. J Exp Med 200:587–599. doi:10.1084/jem.20032236

    Article  CAS  Google Scholar 

  21. Brenchley JM, Price DA, Schacker TW et al (2006) Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 12:1365–1371. doi:10.1038/nm1511

    Article  PubMed  CAS  Google Scholar 

  22. Bofill M, Gombert W, Borthwick NJ, Akbar AN, McLaughlin JE, Lee CA, Johnson MA, Pinching AJ, Janossy G (1995) Presence of CD3+CD8+Bcl-2(low) lymphocytes undergoing apoptosis and activated macrophages in lymph nodes of HIV-1+ patients. Am J Pathol 146:1542–1555

    PubMed  CAS  Google Scholar 

  23. Boudet F, Lecoeur H, Gougeon M-L (1996) Apoptosis associated with ex vivo down-regulation of bcl-2 and up-regulation of Fas in potential cytotoxic CD8+ T lymphocytes during HIV infection. J Immunol 156:2282

    PubMed  CAS  Google Scholar 

  24. Petrovas C, Mueller YM, Dimitriou ID, Bojczuk PM, Mounzer KC, Witek J, Altman JD, Katsikis PD (2004) HIV-specific CD8+ T cells exhibit markedly reduced levels of Bcl-2 and Bcl-xL. J Immunol 172:4444–4453

    PubMed  CAS  Google Scholar 

  25. Mueller YM, Petrovas C, Do DH, Altork SR, Fischer-Smith T, Rappaport J, Altman JD, Lewis MG, Katsikis PD (2007) Early establishment and antigen dependence of simian immunodeficiency virus-specific CD8+ T-cell defects. J Virol 81:10861–10868. doi:10.1128/JVI.00813-07

    Article  PubMed  CAS  Google Scholar 

  26. Genescà M, Rourke T, Li J, Bost K, Chohan B, McChesney MB, Miller CJ (2007) Live attenuated lentivirus infection elicits polyfunctional simian immunodeficiency virus Gag-specific CD8+ T cells with reduced apoptotic susceptibility in rhesus macaques that control virus replication after challenge with pathogenic SIVmac239. J Immunol 179:4732–4740

    PubMed  Google Scholar 

  27. Gougeon ML (2003) Apoptosis as an HIV strategy to escape immune attack. Nat Rev Immunol 3:392–404. doi:10.1038/nri1087

    Article  PubMed  CAS  Google Scholar 

  28. Hardy AW, Graham DR, Shearer GM, Herbeuval JP (2007) HIV turns plasmacytoid dendritic cells (pDC) into TRAIL-expressing killer pDC and down-regulates HIV coreceptors by Toll-like receptor 7-induced IFN-alpha. Proc Natl Acad Sci USA 104:17453–17458. doi:10.1073/pnas.0707244104

    Article  PubMed  CAS  Google Scholar 

  29. Nardacci R, Antinori A, Larocca LM, Arena V, Amendola A, Perfettini JL, Kroemer G, Piacentini M (2005) Characterization of cell death pathways in human immunodeficiency virus-associated encephalitis. Am J Pathol 167:695–704

    PubMed  CAS  Google Scholar 

  30. Perfettini JL, Roumier T, Castedo M et al (2004) NF-{kappa}B and p53 are the dominant apoptosis-inducing transcription factors elicited by the HIV-1 envelope. J Exp Med 199:629–640. doi:10.1084/jem.20031216

    Article  PubMed  CAS  Google Scholar 

  31. Perfettini JL, Castedo M, Nardacci R et al (2005) Essential role of p53 phosphorylation by p38 MAPK in apoptosis induction by the HIV-1 envelope. J Exp Med 201:279–289. doi:10.1084/jem.20041502

    Article  PubMed  CAS  Google Scholar 

  32. Piacentini M, Kroemer G (2005) Cell death pathways in retroviral infection. Cell Death Differ 12:835–836. doi:10.1038/sj.cdd.4401655

    Article  PubMed  Google Scholar 

  33. Perfettini JL, Nardacci R, Bourouba MG et al (2008) Critical involvement of the ATM-dependent DNA damage response in the apoptotic demise of HIV-1-elicited syncytia. PLoS ONE 3(6):e2458. doi:10.1371/journal.pone.0002458

    Article  PubMed  CAS  Google Scholar 

  34. Perfettini JL, Nardacci R, Séror C et al (2008) The tumor suppressor protein PML controls apoptosis induced by the HIV-1 envelope. Cell Death Differ (Nov):21

  35. Deeks SG, Walker BD (2007) Human immunodeficiency virus controllers: mechanisms of durable virus control in the absence of antiretroviral therapy. Immunity 27:406–416. doi:10.1016/j.immuni.2007.08.010

    Article  PubMed  CAS  Google Scholar 

  36. Betts MR, Nason MC, West SM et al (2006) HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood 107:4781–4789. doi:10.1182/blood-2005-12-4818

    Article  PubMed  CAS  Google Scholar 

  37. Migueles SA, Laborico AC, Shupert WL et al (2002) HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nat Immunol 3:1061–1068. doi:10.1038/ni845

    Article  PubMed  CAS  Google Scholar 

  38. Saez-Cirion A, Lacabaratz C, Lambotte O et al (2007) HIV controllers exhibit potent CD8 T cell capacity to suppress HIV infection ex vivo and peculiar cytotoxic T lymphocyte activation phenotype. Proc Natl Acad Sci USA 104:6776–6781. doi:10.1073/pnas.0611244104

    Article  PubMed  CAS  Google Scholar 

  39. Appay V, Nixon DF, Donahoe SM et al (2000) HIV-specific CD8+ T cells produce antiviral cytokines but are impaired in cytolytic function. J Exp Med 192:63–75. doi:10.1084/jem.192.1.63

    Article  PubMed  CAS  Google Scholar 

  40. Champagne P, Ogg GS, King AS et al (2001) Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature 410:106–111. doi:10.1038/35065118

    Article  PubMed  CAS  Google Scholar 

  41. Day CL, Kaufmann DE, Kiepiela P et al (2006) PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443:350–354. doi:10.1038/nature05115

    Article  PubMed  CAS  Google Scholar 

  42. Petrovas C, Casazza JP, Brenchley JM et al (2006) PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J Exp Med 203:2281–2292. doi:10.1084/jem.20061496

    Article  PubMed  CAS  Google Scholar 

  43. Trautmann L, Janbazian L, Chomont N et al (2006) Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med 12:1198–1202. doi:10.1038/nm1482

    Article  PubMed  CAS  Google Scholar 

  44. Gougeon M-L, Montagnier L (1993) Apoptosis in AIDS. Science 260:1269–1270. doi:10.1126/science.8098552

    Article  PubMed  CAS  Google Scholar 

  45. Meyaard L, Otto SA, Jonker RR et al (1992) Programmed death of T cells in HIV-1 infection. Science 257:217–219. doi:10.1126/science.1352911

    Article  PubMed  CAS  Google Scholar 

  46. Rawson PM, Molette C, Videtta M et al (2007) Cross-presentation of caspase-cleaved apoptotic self antigens in HIV infection. Nat Med 13:1431–1439. doi:10.1038/nm1679

    Article  PubMed  CAS  Google Scholar 

  47. Yorimitsu T, Klionsky DJ (2005) Autophagy: molecular machinery for self-eating. Cell Death Differ S2:1542–1552. doi:10.1038/sj.cdd.4401765

    Article  CAS  Google Scholar 

  48. Schmid D, Münz C (2007) Innate and adaptive immunity through autophagy. Immunity 27:11–21. doi:10.1016/j.immuni.2007.07.004

    Article  PubMed  CAS  Google Scholar 

  49. Lee HK, Lund JM, Ramanathan B, Mizushima N, Iwasaki A (2007) Autophagy-dependent viral recognition by plasmacytoid dendritic cells. Science 315:1398–1401. doi:10.1126/science.1136880

    Article  PubMed  CAS  Google Scholar 

  50. Denizot M, Varbanov M, Espert L (2008) HIV-1 gp41 fusogenic function triggers autophagy in uninfected cells. Autophagy 4:998–1008

    PubMed  CAS  Google Scholar 

  51. Zhou D, Spector SA (2008) Human immunodeficiency virus type-1 infection inhibits autophagy. AIDS 22:695–699

    Article  PubMed  CAS  Google Scholar 

  52. Kroemer G, Levine B (2008) Autophagic cell death: the story of a misnomer. Nat Rev Mol Cell Biol 9:1004–1010. doi:10.1038/nrm2529

    Article  PubMed  CAS  Google Scholar 

  53. Sarkar S, Rubinsztein DC (2008) Huntington’s disease: degradation of mutant huntingtin by autophagy. FEBS J 275:4263–4270. doi:10.1111/j.1742-4658.2008.06562.x

    Article  PubMed  CAS  Google Scholar 

  54. Fimia GM, Stoykova A, Romagnoli A et al (2007) Ambra1 regulates autophagy and development of the nervous system. Nature 447:1121–1125

    PubMed  CAS  Google Scholar 

  55. Gonzalez-Scarano F, Martin-Garcia J (2005) The neuropathogenesis of AIDS. Nat Rev Immunol 5:69–81. doi:10.1038/nri1527

    Article  PubMed  CAS  Google Scholar 

  56. Alirezaei M, Kiosses WB, Fox HS (2008) Decreased neuronal autophagy in HIV dementia: a mechanism of indirect neurotoxicity. Autophagy 4:963–966

    PubMed  CAS  Google Scholar 

  57. Freeman GJ, Wherry EJ, Ahmed R, Sharpe AH (2006) Reinvigorating exhausted HIV-specific T cells via PD-1–PD-1 ligand blockade. J Exp Med 203:2223–2227. doi:10.1084/jem.20061800

    Article  PubMed  CAS  Google Scholar 

  58. Ledru E, Christeff N, Patey O, de Truchis P, Melchior JC, Gougeon ML (2000) Alteration of tumor necrosis factor-alpha T-cell homeostasis following potent antiretroviral therapy: contribution to the development of human immunodeficiency virus-associated lipodystrophy syndrome. Blood 95:3191–3198

    PubMed  CAS  Google Scholar 

  59. Brass AL, Dykxhoorn DM, Benita Y et al (2008) Identification of host proteins required for HIV infection through a functional genomic screen. Science 319:921–926. doi:10.1126/science.1152725

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from Sidaction and Agence Nationale de la Recherche (ANR no. 07-RARE-002-01) to MLG, Ricerca Corrente and Finalizzata from Ministero della Salute, AIRC, Telethon Foundation, EU integrated project “Apo-sys” to MP.

Author information

Authors and Affiliations

  1. Antiviral Immunity, Biotherapy and Vaccine Unit, Institut Pasteur, Paris, France

    M.-L. Gougeon

  2. Department of Biology, University of Rome “Tor Vergata” and National Institute for Infectious Diseases, IRCCS “Lazzaro Spallanzani”, Rome, Italy

    M. Piacentini

Authors
  1. M.-L. Gougeon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Piacentini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M.-L. Gougeon.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gougeon, ML., Piacentini, M. New insights on the role of apoptosis and autophagy in HIV pathogenesis. Apoptosis 14, 501–508 (2009). https://doi.org/10.1007/s10495-009-0314-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-009-0314-1

Keywords

Search

Navigation