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Current HIV/AIDS Reports

, Volume 8, Issue 1, pp 4–11 | Cite as

Revisiting Immune Exhaustion During HIV Infection

  • Alka Khaitan
  • Derya Unutmaz
Article

Abstract

Chronic immune activation is a hallmark of HIV infection, yet the underlying triggers of immune activation remain unclear. Persistent antigenic stimulation during HIV infection may also lead to immune exhaustion, a phenomenon in which effector T cells become dysfunctional and lose effector functions and proliferative capacity. Several markers of immune exhaustion, such as PD-1, LAG-3, Tim-3, and CTLA-4, which are also negative regulators of immune activation, are preferentially upregulated on T cells during HIV infection. It is not yet clear whether accumulation of T cells expressing activation inhibitory molecules is a consequence of general immune or chronic HIV-specific immune activation. Importantly, however, in vitro blockade of PD-1 and Tim-3 restores HIV-specific T-cell responses, indicating potential for immunotherapies. In this review we discuss the evolution of our understanding of immune exhaustion during HIV infection, highlighting novel markers and potential therapeutic targets.

Keywords

T-cell exhaustion Immune activation PD-1 Tim-3 HIV LAG-3 SIV 

Notes

Acknowledgments

This work was supported by NIH grant R21AI087973-01 to DU and the NYU Physician Scientist Training Program award to AK, supported in part by grant 1 UL1 RR029893 from the National Center for Research Resources, National Institutes of Health.

Disclosure

No potential conflicts of interest relevant to this article were reported.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Lane HC, Masur H, Edgar LC, et al. Abnormalities of B-cell activation and immunoregulation in patients with the acquired immunodeficiency syndrome. N Engl J Med. 1983;309(8):453–8.CrossRefPubMedGoogle Scholar
  2. 2.
    Hellerstein M, Hanley MB, Cesar D, et al. Directly measured kinetics of circulating T lymphocytes in normal and HIV-1-infected humans. Nat Med. 1999;5(1):83–9.CrossRefPubMedGoogle Scholar
  3. 3.
    Hazenberg MD, Stuart JW, Otto SA, et al. 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. 2000;95(1):249–55.PubMedGoogle Scholar
  4. 4.
    Valdez H, Lederman MM. Cytokines and cytokine therapies in HIV infection. AIDS Clin Rev. 1997:187–228.Google Scholar
  5. 5.
    Giorgi JV, Liu Z, Hultin LE, et al. Elevated levels of CD38+ CD8+ T cells in HIV infection add to the prognostic value of low CD4+ T cell levels: results of 6 years of follow-up. The Los Angeles Center, Multicenter AIDS Cohort Study. J Acquir Immune Defic Syndr. 1993;6(8):904–12.PubMedGoogle Scholar
  6. 6.
    Giorgi JV, Hultin LE, McKeating JA, et al. 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. 1999;179(4):859–70.CrossRefPubMedGoogle Scholar
  7. 7.
    Silvestri G, Sodora DL, Koup RA, et al. Nonpathogenic SIV infection of sooty mangabeys is characterized by limited bystander immunopathology despite chronic high-level viremia. Immunity. 2003;18(3):441–52.CrossRefPubMedGoogle Scholar
  8. 8.
    Legrand FA, Nixon DF, Loo CP, et al. Strong HIV-1-specific T cell responses in HIV-1-exposed uninfected infants and neonates revealed after regulatory T cell removal. PLoS One. 2006;1:e102. PMCID: 1762312CrossRefPubMedGoogle Scholar
  9. 9.
    Aandahl EM, Michaelsson J, Moretto WJ, et al. Human CD4+ CD25+ regulatory T cells control T-cell responses to human immunodeficiency virus and cytomegalovirus antigens. J Virol. 2004;78(5):2454–9. PMCID: 369239.CrossRefPubMedGoogle Scholar
  10. 10.
    Kinter AL, Hennessey M, Bell A, et al. CD25(+)CD4(+) regulatory T cells from the peripheral blood of asymptomatic HIV-infected individuals regulate CD4(+) and CD8(+) HIV-specific T cell immune responses in vitro and are associated with favorable clinical markers of disease status. J Exp Med. 2004;200(3):331–43. PMCID: 2211981.CrossRefPubMedGoogle Scholar
  11. 11.
    Weiss L, Donkova-Petrini V, Caccavelli L, et al. Human immunodeficiency virus-driven expansion of CD4 + CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients. Blood. 2004;104(10):3249–56.CrossRefPubMedGoogle Scholar
  12. 12.
    Oswald-Richter K, Grill SM, Shariat N, et al. HIV infection of naturally occurring and genetically reprogrammed human regulatory T-cells. PLoS Biol. 2004;2(7):E198. PMCID: 449855.CrossRefPubMedGoogle Scholar
  13. 13.
    Eggena MP, Barugahare B, Jones N, et al. Depletion of regulatory T cells in HIV infection is associated with immune activation. J Immunol. 2005;174(7):4407–14.PubMedGoogle Scholar
  14. 14.
    Swiecki M, Colonna M. Unraveling the functions of plasmacytoid dendritic cells during viral infections, autoimmunity, and tolerance. Immunol Rev. 2010;234(1):142–62.CrossRefPubMedGoogle Scholar
  15. 15.
    El Hed A, Khaitan A, Kozhaya L, et al. Susceptibility of human Th17 cells to human immunodeficiency virus and their perturbation during infection. J Infect Dis. 2010;201(6):843–54. PMCID: 2849315.CrossRefPubMedGoogle Scholar
  16. 16.
    Brenchley JM, Price DA, Schacker TW, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006;12(12):1365–71.CrossRefPubMedGoogle Scholar
  17. 17.
    Wherry EJ, Blattman JN, Murali-Krishna K, van der Most R, Ahmed R. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol. 2003;77(8):4911–27. PMCID: 152117.CrossRefPubMedGoogle Scholar
  18. 18.
    •• Wherry EJ, Ha SJ, Kaech SM, et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity. 2007;27(4):670–84. This is the study that identified several markers of immune exhaustion by a microarray analysis of dysfunctional CD8+ T cells during LCMV infection. PD-1 was the most prominent gene identified.CrossRefPubMedGoogle Scholar
  19. 19.
    Zajac AJ, Blattman JN, Murali-Krishna K, et al. Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med. 1998;188(12):2205–13. PMCID: 2212420CrossRefPubMedGoogle Scholar
  20. 20.
    Urbani S, Amadei B, Tola D, et al. PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion. J Virol. 2006;80(22):11398–403. PMCID: 1642188.CrossRefPubMedGoogle Scholar
  21. 21.
    Radziewicz H, Ibegbu CC, Fernandez ML, et al. Liver-infiltrating lymphocytes in chronic human hepatitis C virus infection display an exhausted phenotype with high levels of PD-1 and low levels of CD127 expression. J Virol. 2007;81(6):2545–53. PMCID: 1865979.CrossRefPubMedGoogle Scholar
  22. 22.
    Boni C, Fisicaro P, Valdatta C, et al. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J Virol. 2007;81(8):4215–25. PMCID: 1866111.CrossRefPubMedGoogle Scholar
  23. 23.
    •• Day CL, Kaufmann DE, Kiepiela P, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature. 2006;443(7109):350-4. This study showed that PD-1 was expressed on HIV-specific CD8+ and CD4+ T cells and correlated with markers of HIV disease progression. HIV-specific CD4+ and CD8+ T-cell responses rescued with blockade of PD-1. CrossRefPubMedGoogle Scholar
  24. 24.
    •• Trautmann L, Janbazian L, Chomont N, et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med. 2006;12(10):1198–202. This study showed that PD-1 was upregulated on HIV-specific but not CMV-specific CD8+ T cells and correlated with markers of HIV disease progression. Blocking PD-1 resulted in enhanced survival, proliferation, and cytokine secretion by HIV-specific CD8+ T cells. CrossRefPubMedGoogle Scholar
  25. 25.
    El-Far M, Halwani R, Said E, et al. T-cell exhaustion in HIV infection. Curr HIV/AIDS Rep. 2008;5(1):13–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992;11(11):3887–95. PMCID: 556898.PubMedGoogle Scholar
  27. 27.
    Kaufmann DE, Walker BD. Programmed death-1 as a factor in immune exhaustion and activation in HIV infection. Curr Opin HIV AIDS. 2008;3(3):362–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Nishimura H, Nose M, Hiai H, et al. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999;11(2):141–51.CrossRefPubMedGoogle Scholar
  29. 29.
    Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol. 2007;8(3):239–45.CrossRefPubMedGoogle Scholar
  30. 30.
    •• Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439(7077):682–7. This study reported that T-cell exhaustion mediated by PD-1 was reversible by in vitro blockade of PD-1 in the murine LCMV model. CrossRefPubMedGoogle Scholar
  31. 31.
    Monney L, Sabatos CA, Gaglia JL, et al. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature. 2002;415(6871):536–41.CrossRefPubMedGoogle Scholar
  32. 32.
    Zhu C, Anderson AC, Schubart A, et al. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol. 2005;6(12):1245–52.CrossRefPubMedGoogle Scholar
  33. 33.
    Sabatos CA, Chakravarti S, Cha E, et al. Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance. Nat Immunol. 2003;4(11):1102–10.CrossRefPubMedGoogle Scholar
  34. 34.
    Hafler DA, Kuchroo V. TIMs: central regulators of immune responses. J Exp Med. 2008;205(12):2699–701. PMCID: 2585854CrossRefPubMedGoogle Scholar
  35. 35.
    •• Hastings WD, Anderson DE, Kassam N, et al. TIM-3 is expressed on activated human CD4+ T cells and regulates Th1 and Th17 cytokines. Eur J Immunol. 2009;39(9):2492–501. PMCID: 2759376. This report was the first to demonstrate Tim-3 is a negative regulator of Th1 and Th17 cells. They showed Tim-3 was expressed on activated Th17 cells in addition to Th1 cells. Activated CD4+ T cells cultured with monoclonal antibodies to Tim-3 increased IL-17, IFNγ, IL-2, and IL-6 but not Il-10 secretion. CrossRefPubMedGoogle Scholar
  36. 36.
    Tesmer LA, Lundy SK, Sarkar S, Fox DA. Th17 cells in human disease. Immunol Rev. 2008;223:87–113.CrossRefPubMedGoogle Scholar
  37. 37.
    Durelli L, Conti L, Clerico M, et al. T-helper 17 cells expand in multiple sclerosis and are inhibited by interferon-beta. Ann Neurol. 2009;65(5):499–509.CrossRefPubMedGoogle Scholar
  38. 38.
    Koguchi K, Anderson DE, Yang L, et al. Dysregulated T cell expression of TIM3 in multiple sclerosis. J Exp Med. 2006;203(6):1413–8. PMCID: 2118310.CrossRefPubMedGoogle Scholar
  39. 39.
    •• Blackburn SD, Shin H, Haining WN, et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol. 2009;10(1):29–37. PMCID: 2605166. This report demonstrates that exhausted T cells coexpress multiple negative regulators and coexpression is associated with more severe T-cell exhaustion and infection. Dual blockade of PD-1 and LAG-3 synergistically improved CD8+ T-cell function and lowered viral load in the LCMV murine model. CrossRefPubMedGoogle Scholar
  40. 40.
    • Richter K, Agnellini P, Oxenius A. On the role of the inhibitory receptor LAG-3 in acute and chronic LCMV infection. Int Immunol. 2010;22(1):13–23. This review discusses the role of LAG-3 during LCMV infection. CrossRefPubMedGoogle Scholar
  41. 41.
    Romagnani S. Th1 and Th2 in human diseases. Clin Immunol Immunopathol. 1996;80(3 Pt 1):225–35.CrossRefPubMedGoogle Scholar
  42. 42.
    Zhang JY, Zhang Z, Wang X, et al. PD-1 up-regulation is correlated with HIV-specific memory CD8+ T-cell exhaustion in typical progressors but not in long-term nonprogressors. Blood. 2007;109(11):4671–8.CrossRefPubMedGoogle Scholar
  43. 43.
    • Petrovas C, Price DA, Mattapallil J, et al. SIV-specific CD8+ T cells express high levels of PD1 and cytokines but have impaired proliferative capacity in acute and chronic SIVmac251 infection. Blood. 2007;110(3):928–36. PMCID: 1924769. This study demonstrated the in vivo relevance of PD-1 in the non-human primate model of SIV infection. SIV-specific CD8+ T cells with high levels of PD-1 expression had low proliferative capacity compared with PD-1(low) T cells. SIV epitopes with mutational escapes led to decreased PD-1 expression, showing that repeated TCR stimulation is a crucial factor in PD-1 expression. CrossRefPubMedGoogle Scholar
  44. 44.
    • Velu V, Kannanganat S, Ibegbu C, et al. Elevated expression levels of inhibitory receptor programmed death 1 on simian immunodeficiency virus-specific CD8 T cells during chronic infection but not after vaccination. J Virol. 2007;81(11):5819–28. PMCID: 1900286. During SIV infection in macaques, this study reports the majority of SIV-specific CD8+ T cells express PD-1. Levels of PD-1 were highest in the lymph nodes and rectal mucosa and correlated with plasma viremia. They also showed that in vitro blockade of PD-1 enhanced SIV-specific CD8+ and CD4+ T-cell proliferation. CrossRefPubMedGoogle Scholar
  45. 45.
    •• Velu V, Titanji K, Zhu B, et al. Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature. 2009;458(7235):206–10. PMCID: 2753387. This was the first in vivo trial of the safety and immune restoration potential of PD-1 blockade in macaques with chronic SIV infection. PD-1 blockade was well tolerated by macaques and resulted in rapid expansion of HIV-specific CD8+ T cells with improved polyfunctionality, thus establishing both safety and efficacy of PD-1 blockade in the SIV/macaque model. CrossRefPubMedGoogle Scholar
  46. 46.
    Estes JD, Gordon SN, Zeng M, et al. Early resolution of acute immune activation and induction of PD-1 in SIV-infected sooty mangabeys distinguishes nonpathogenic from pathogenic infection in rhesus macaques. J Immunol. 2008;180(10):6798–807. PMCID: 2596686.PubMedGoogle Scholar
  47. 47.
    • Said EA, Dupuy FP, Trautmann L, et al. Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection. Nat Med. 2010;16(4):452–9. In this study the authors demonstrate that PD-L1 triggering of PD-1 expressed on monocytes induced IL-10 production and reversible CD4+ T-cell dysfunction. They also show that HIV-infected individuals have high PD-1 expression on monocytes, which may be triggered by products of microbial translocation. CrossRefPubMedGoogle Scholar
  48. 48.
    • Jones RB, Ndhlovu LC, Barbour JD, et al. Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection. J Exp Med. 2008;205(12):2763–79.PMCID: 2585847. This was the first study of Tim-3 in HIV-infected individuals, showing elevated levels of Tim-3 on CD8+ T cells in HIV+ individuals that correlated with CD4+ T cells and HIV viral load. Blockade of Tim-3 resulted in improved HIV-specific CD8+ T-cell responses. CrossRefPubMedGoogle Scholar
  49. 49.
    Price P, Keane N, Gray L, et al. CXCR4 or CCR5 tropism of human immunodeficiency virus type 1 isolates does not determine the immunological milieu in patients responding to antiretroviral therapy. Viral Immunol. 2006;19(4):734–40.CrossRefPubMedGoogle Scholar
  50. 50.
    Lim AY, Price P, Beilharz MW, French MA. Cell surface markers of regulatory T cells are not associated with increased forkhead box p3 expression in blood CD4+ T cells from HIV-infected patients responding to antiretroviral therapy. Immunol Cell Biol. 2006;84(6):530–6.CrossRefPubMedGoogle Scholar
  51. 51.
    • Antonelli LR, Mahnke Y, Hodge JN, et al. Elevated frequencies of highly activated CD4+ T cells in HIV+ patients developing immune reconstitution inflammatory syndrome. Blood. 2010. This report demonstrated that in HIV-infected individuals initiating antiretroviral therapy, those who developed immune reconstitution syndrome had higher baseline levels of PD-1 with CTLA-4 and LAG-3 coexpression on CD4+ T cells. Google Scholar
  52. 52.
    • Jin HT, Anderson AC, Tan WG, et al. Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proc Natl Acad Sci USA 2010;107(33):14733–8. In this study, the authors evaluate Tim-3 and PD-1 coexpression during LCMV infection in the mouse, showing PD-1+Tim-3+ CD8+ T cells had more severe T-cell exhaustion. Combined inhibition of PD-1 and Tim-3 synergistically improved CD8+ T-cell responses. CrossRefPubMedGoogle Scholar
  53. 53.
    Vali B, Jones RB, Sakhdari A, et al. HCV-specific T cells in HCV/HIV co-infection show elevated frequencies of dual Tim-3/PD-1 expression that correlate with liver disease progression. Eur J Immunol. 2010.Google Scholar
  54. 54.
    Sachdeva M, Fischl MA, Pahwa R, et al. Immune exhaustion occurs concomitantly with immune activation and decrease in regulatory T cells in viremic chronically HIV-1-infected patients. J Acquir Immune Defic Syndr. 2010;54(5):447–54.CrossRefPubMedGoogle Scholar
  55. 55.
    Vollbrecht T, Brackmann H, Henrich N, et al. Impact of changes in antigen level on CD38/PD-1 co-expression on HIV-specific CD8 T cells in chronic, untreated HIV-1 infection. J Med Virol. 2010;82(3):358–70.CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of PediatricsNew York University School of MedicineNew YorkUSA
  2. 2.Department of MicrobiologyNew York University School of MedicineNew YorkUSA
  3. 3.Department of PathologyNew York University School of MedicineNew YorkUSA
  4. 4.Department of MedicineNew York University School of MedicineNew YorkUSA
  5. 5.New York University Langone Medical CenterNew YorkUSA

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