Skip to main content

Advertisement

Log in

Advances in understanding immunologic control of HIV infection

  • Published:
Current HIV/AIDS Reports Aims and scope Submit manuscript

Abstract

Over the past several years, the progress made in understanding the cellular immune response to HIV is likely greater compared to any other time since the beginning of the worldwide epidemic. This progress has largely been made possible by technical advances that have permitted a much more quantitative and highly detailed study of virus-specific cellular immunity in humans than was previously available. However, despite intensive study of the HIV-specific cellular immune response, we do not fully understand the nature of immunologic control in some rare cases and lack of control in most of untreated patients. It has become increasingly clear that HIV replication is poorly controlled in most untreated patients, despite a high-frequency HIV-specific cellular immune response. Therefore, attention has turned to qualitative features of the immune response that may dictate restriction of viral replication. Because most vaccines in preclinical or clinical testing rely on cellular immune responses that may alter disease progression but are unlikely to prevent infection, understanding these qualitative features is of particular importance. Further study could yield critical information for inducing effective immunity in vaccinees, preventing the loss of control of viral replication on the infection of vaccinees, or inducing immunologic control in infected humans.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

  1. Migueles SA, Connors M: The role of CD4(+) and CD8(+) T cells in controlling HIV infection. Curr Infect Dis Rep 2002, 4:461–467.

    PubMed  Google Scholar 

  2. Letvin NL, Walker BD: Immunopathogenesis and immunotherapy in AIDS virus infections. Nat Med 2003, 9:861–866.

    Article  PubMed  CAS  Google Scholar 

  3. Lieberman J, Shankar P, Manjunath N, Andersson J: Dressed to kill? A review of why antiviral CD8 T lymphocytes fail to prevent progressive immunodeficiency in HIV-1 infection. Blood 2001, 98:1667–1677.

    Article  PubMed  CAS  Google Scholar 

  4. Kaech SM, Ahmed R: Immunology: CD8 T cells remember with a little help. Science 2003, 300:263–265.

    Article  PubMed  CAS  Google Scholar 

  5. Rosenberg ES, Billingsley JM, Caliendo AM, et al.: Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science 1997, 278:1447–1450.

    Article  PubMed  CAS  Google Scholar 

  6. Rosenberg ES, Altfeld M, Poon SH, et al.: Immune control of HIV-1 after early treatment of acute infection. Nature 2000, 407:523–526.

    Article  PubMed  CAS  Google Scholar 

  7. Oxenius A, Price DA, Easterbrook PJ, et al.: Early highly active antiretroviral therapy for acute HIV-1 infection preserves immune function of CD8+ and CD4+ T lymphocytes. Proc Natl Acad Sci U S A 2000, 97:3382–3387.

    Article  PubMed  CAS  Google Scholar 

  8. Douek DC, Brenchley JM, Betts MR, et al.: HIV preferentially infects HIV-specific CD4+ T cells. Nature 2002, 417:95–98.

    Article  PubMed  CAS  Google Scholar 

  9. Betts MR, Ambrozak DR, Douek DC, et al.: Analysis of total human immunodeficiency virus (HIV)-specific CD4(+) and CD8(+) T-cell responses: relationship to viral load in untreated HIV infection. J Virol 2001, 75:11983–11991.

    Article  PubMed  CAS  Google Scholar 

  10. Pitcher CJ, Quittner C, Peterson DM, et al.: HIV-1-specific CD4+ T cells are detectable in most individuals with active HIV-1 infection, but decline with prolonged viral suppression. Nat Med 1999, 5:518–525.

    Article  PubMed  CAS  Google Scholar 

  11. Wilson JD, Imami N, Watkins A, et al.: Loss of CD4+ T cell proliferative ability but not loss of human immunodeficiency virus type 1 specificity equates with progression to disease. J Infect Dis 2000, 182:792–798.

    Article  PubMed  CAS  Google Scholar 

  12. McNeil AC, Shupert WL, Iyasere CA, et al.: High-level HIV-1 viremia suppresses viral antigen-specific CD4+ T cell proliferation. Proc Natl Acad Sci U S A 2001, 98:13878–13883.

    Article  PubMed  CAS  Google Scholar 

  13. Palmer BE, Boritz E, Blyveis N, Wilson CC: Discordance between frequency of human immunodeficiency virus type 1 (HIV-1)-specific gamma interferon-producing CD4(+) T cells and HIV-1-specific lymphoproliferation in HIV-1-infected subjects with active viral replication. J Virol 2002, 76:5925–5936.

    Article  PubMed  CAS  Google Scholar 

  14. Lange CG, Valdez H, Medvik K, et al.: CD4+ T-lymphocyte nadir and the effect of highly active antiretroviral therapy on phenotypic and functional immune restoration in HIV-1 infection. Clin Immunol 2002, 102:154–161.

    Article  PubMed  CAS  Google Scholar 

  15. Blankson JN, Gallant JE, Siliciano RF: Proliferative responses to human immunodeficiency virus type 1 (HIV-1) antigens in HIV-1-infected patients with immune reconstitution. J Infect Dis 2001, 183:657–661.

    Article  PubMed  CAS  Google Scholar 

  16. Binley JM, Schiller DS, Ortiz GM, et al.: The relationship between T-cell proliferative responses and plasma viremia during treatment of human immunodeficiency virus type 1 infection with combination antiretroviral therapy. J Infect Dis 2000, 181:1249–1263.

    Article  PubMed  CAS  Google Scholar 

  17. Al-Harthi L, Siegel J, Spritzler J, et al.: Maximum suppression of HIV replication leads to the restoration of HIV-specific responses in early HIV disease. AIDS 2000, 14:761–770.

    Article  PubMed  CAS  Google Scholar 

  18. Markowitz M, Jin X, Hurley A, et al.: Discontinuation of antiretroviral therapy commenced early during the course of human immunodeficiency virus type 1 infection, with or without adjunctive vaccination. J Infect Dis 2002, 186:634–643.

    Article  PubMed  CAS  Google Scholar 

  19. Iyasere CA, Tilton J, Johnson AJ, et al.: Diminished proliferation of HIV-specific CD4+ T cells is associated with diminished interleukin-2 (IL-2) production and is recovered by exogenous IL-2. J Virol 2003, 77:10900–10909.

    Article  PubMed  CAS  Google Scholar 

  20. Asanuma H, Sharp M, Maecker HT, et al.: Frequencies of memory T cells specific for varicella-zoster virus, herpes simplex virus, and cytomegalovirus by intracellular detection of cytokine expression. J Infect Dis 2000, 181:859–866.

    Article  PubMed  CAS  Google Scholar 

  21. Kern F, Bunde T, Faulhaber N, et al.: Cytomegalovirus (CMV) phosphoprotein 65 makes a large contribution to shaping the T cell repertoire in CMV-exposed individuals. J Infect Dis 2002, 185:1709–1716.

    Article  PubMed  CAS  Google Scholar 

  22. Komanduri KV, Donahoe SM, Moretto WJ, et al.: Direct measurement of CD4+ and CD8+ T-cell responses to CMV in HIV-1-infected subjects. Virology 2001, 279:459–470.

    Article  PubMed  CAS  Google Scholar 

  23. Scott ZA, Beaumier CM, Sharkey M, et al.: HIV-1 replication increases HIV-specific CD4(+) T cell frequencies but limits proliferative capacity in chronically infected children. J Immunol 2003, 170:5786–5792.

    PubMed  CAS  Google Scholar 

  24. Younes SA, Yassine-Diab B, Dumont AR, et al.: HIV-1 viremia prevents the establishment of interleukin 2-producing HIV-specific memory CD4+ T cells endowed with proliferative capacity. J Exp Med 2003, 198:1909–1922.

    Article  PubMed  CAS  Google Scholar 

  25. Harari A, Petitpierre S, Vallelian F, Pantaleo G: Skewed representation of functionally distinct populations of virus-specific CD4 T cells in HIV-1-infected subjects with progressive disease: changes after antiretroviral therapy. Blood 2004, 103:966–972.

    Article  PubMed  CAS  Google Scholar 

  26. Boaz MJ, Waters A, Murad S, et al.: Presence of HIV-1 Gagspecific IFN-gamma+IL-2+ and CD28+IL-2+ CD4 T cell responses is associated with nonprogression in HIV-1 infection. J Immunol 2002, 169:6376–6385.

    PubMed  CAS  Google Scholar 

  27. Koup RA, Safrit JT, Cao Y, et al.: Temporal association of cellular immune response with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol 1994, 68:4650–4655.

    PubMed  CAS  Google Scholar 

  28. Schmitz JE, Kuroda MJ, Santra S, et al.: Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 1999, 283:857–860.

    Article  PubMed  CAS  Google Scholar 

  29. Jin X, Bauer DE, Tuttleton SE, et al.: Dramatic rise in plasma viremia after CD8(+) T-cell depletion in simian immunodeficiency virus-infected macaques. J Exp Med 1999, 189:991–998.

    Article  PubMed  CAS  Google Scholar 

  30. Migueles SA, Sabbaghian MS, Shupert WL, et al.: HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long-term nonprogressors. Proc Natl Acad Sci U S A 2000, 97:2709–2714.

    Article  PubMed  CAS  Google Scholar 

  31. Goulder PJ, Bunce M, Krausa P, et al.: Novel, cross-restricted, conserved, and immunodominant cytotoxic T lymphocyte epitopes in slow progressors in HIV type 1 infection. AIDS Res Hum Retroviruses 1996, 12:1691–1698.

    Article  PubMed  CAS  Google Scholar 

  32. Dalod M, Dupuis M, Deschemin JC, et al.: Broad, intense anti-human immunodeficiency virus (HIV) ex vivo CD8(+) responses in HIV type 1-infected patients: comparison with anti-Epstein-Barr virus responses and changes during antiretroviral therapy. J Virol 1999, 73:7108–7116.

    PubMed  CAS  Google Scholar 

  33. Gea-Banacloche JC, Migueles SA, Martino L, et al.: Maintenance of large numbers of virus-specific CD8+ T cells in HIVinfected progressors and long-term nonprogressors. J Immunol 2000, 165:1082–1092.

    PubMed  CAS  Google Scholar 

  34. Migueles SA, Connors M: Frequency and function of HIVspecific CD8(+) T cells. Immunol Lett 2001, 79:141–150.

    Article  PubMed  CAS  Google Scholar 

  35. Kostense S, Vandenberghe K, Joling J, et al.: Persistent numbers of tetramer+ CD8(+) T cells, but loss of interferon-gamma+ HIV-specific T cells during progression to AIDS. Blood 2002, 99:2505–2511.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  37. Addo MM, Yu XG, Rathod A, et al.: Comprehensive epitope analysis of human immunodeficiency virus type 1 (HIV-1)-specific T-cell responses directed against the entire expressed HIV-1 genome demonstrate broadly directed responses, but no correlation to viral load. J Virol 2003, 77:2081–2092.

    Article  PubMed  CAS  Google Scholar 

  38. Draenert R, Verrill CL, Tang Y, et al.: Persistent recognition of autologous virus by high-avidity CD8 T cells in chronic, progressive human immunodeficiency virus type 1 infection. J Virol 2004, 78:630–641.

    Article  PubMed  CAS  Google Scholar 

  39. Migueles SA, Laborico AC, Imamichi H, et al.: The differential ability of HLA B*5701+ long-term nonprogressors and progressors to restrict human immunodeficiency virus replication is not caused by loss of recognition of autologous viral gag sequences. J Virol 2003, 77:6889–6898.

    Article  PubMed  CAS  Google Scholar 

  40. Lee SK, Xu Z, Lieberman J, Shankar P: The functional CD8 T cell response to HIV becomes type-specific in progressive disease. J Clin Invest 2002, 110:1339–1347.

    Article  PubMed  CAS  Google Scholar 

  41. Yusim K, Kesmir C, Gaschen B, et al.: Clustering patterns of cytotoxic T-lymphocyte epitopes in human immunodeficiency virus type 1 (HIV-1) proteins reveal imprints of immune evasion on HIV-1 global variation. J Virol 2002, 76:8757–8768.

    Article  PubMed  CAS  Google Scholar 

  42. Goulder PJ, Phillips RE, Colbert RA, et al.: Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS. Nat Med 1997, 3:212–217.

    Article  PubMed  CAS  Google Scholar 

  43. Goulder PJ, Brander C, Tang Y, et al.: Evolution and transmission of stable CTL escape mutations in HIV infection. Nature 2001, 412:334–338.

    Article  PubMed  CAS  Google Scholar 

  44. Kelleher AD, Long C, Holmes EC, et al.: Clustered mutations in HIV-1 gag are consistently required for escape from HLA-B27-restricted cytotoxic T lymphocyte responses. J Exp Med 2001, 193:375–386.

    Article  PubMed  CAS  Google Scholar 

  45. van Lier RA, ten Berge IJ, Gamadia LE: Human CD8(+) T-cell differentiation in response to viruses. Nat Rev Immunol 2003, 3:931–939. This paper is a comprehensive overview of the surface phenotype of virus-specific CD8+ T cells in humans.

    Article  PubMed  Google Scholar 

  46. Champagne P, Ogg GS, King AS, et al.: Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature 2001, 410:106–111.

    Article  PubMed  CAS  Google Scholar 

  47. Appay V, Nixon DF, Donahoe SM, et al.: HIV-specific CD8(+) T cells produce antiviral cytokines but are impaired in cytolytic function. J Exp Med 2000, 192:63–76.

    Article  PubMed  CAS  Google Scholar 

  48. van Baarle D, Kostense S, van Oers MH, et al.: Failing immune control as a result of impaired CD8+ T-cell maturation: CD27 might provide a clue. Trends Immunol 2002, 23:586–591.

    Article  PubMed  Google Scholar 

  49. Appay V, Dunbar PR, Callan M, et al.: Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nat Med 2002, 8:379–385.

    Article  PubMed  CAS  Google Scholar 

  50. Callan MF, Tan L, Annels N, et al.: Direct visualization of antigen-specific CD8+ T cells during the primary immune response to Epstein-Barr virus in vivo. J Exp Med 1998, 187:1395–1402.

    Article  PubMed  CAS  Google Scholar 

  51. Faint JM, Annels NE, Curnow SJ, et al.: Memory T cells constitute a subset of the human CD8+CD45RA+ pool with distinct phenotypic and migratory characteristics. J Immunol 2001, 167:212–220.

    PubMed  CAS  Google Scholar 

  52. Trimble LA, Shankar P, Patterson M, et al.: Human immunodeficiency virus-specific circulating CD8 T lymphocytes have down-modulated CD3zeta and CD28, key signaling molecules for T-cell activation. J Virol 2000, 74:7320–7330.

    Article  PubMed  CAS  Google Scholar 

  53. Sandberg JK, Fast NM, Nixon DF: Functional heterogeneity of cytokines and cytolytic effector molecules in human CD8+ T lymphocytes. J Immunol 2001, 167:181–187.

    PubMed  CAS  Google Scholar 

  54. Zhang D, Shankar P, Xu Z, et al.: Most antiviral CD8 T cells during chronic viral infection do not express high levels of perforin and are not directly cytotoxic. Blood 2003, 101:226–235.

    Article  PubMed  CAS  Google Scholar 

  55. Ferrari G, Humphrey W, McElrath MJ, et al.: Clade B-based HIV-1 vaccines elicit cross-clade cytotoxic T lymphocyte reactivities in uninfected volunteers. Proc Natl Acad Sci U S A 1997, 94:1396–1401.

    Article  PubMed  CAS  Google Scholar 

  56. Shankar P, Xu Z, Lieberman J: Viral-specific cytotoxic T lymphocytes lyse human immunodeficiency virus-infected primary T lymphocytes by the granule exocytosis pathway. Blood 1999, 94:3084–3093.

    PubMed  CAS  Google Scholar 

  57. Wherry EJ, Teichgraber V, Becker TC, et al.: Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat Immunol 2003, 4:225–234. This paper examines the temporal nature, functional phenotype, and lineage relationship of CD8+ T cells that restrict lymphocytic choriomeningitis virus replication.

    Article  PubMed  CAS  Google Scholar 

  58. Haigwood NL, Watson A, Sutton WF, et al.: Passive immune globulin therapy in the SIV/macaque model: early intervention can alter disease profile. Immunol Lett 1996, 51:107–114.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Migueles, S.A., Tilton, J.C. & Connors, M. Advances in understanding immunologic control of HIV infection. Curr HIV/AIDS Rep 1, 12–17 (2004). https://doi.org/10.1007/s11904-004-0002-2

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11904-004-0002-2

Keywords

Navigation