Current Infectious Disease Reports

, Volume 4, Issue 5, pp 461–467

The role of CD4+ and CD8+ T cells in controlling HIV infection

  • Stephen A. Migueles
  • Mark Connors


Presently, it is thought that virus-specific T cells play a major role in restricting lentiviral replication and determining the rate of disease progression in humans. However, it remains unclear why this restriction fails in the majority of infected individuals. The major exception is a rare subgroup of HIV-infected long-term nonprogressors (LTNPs) who have been infected for approximately 20 years yet maintain normal CD4+ T-cell counts and less than 50 copies of viral RNA/mL of plasma. Although virus-specific cellular (CD4+ and CD8+ T lymphocytes) immune responses have been shown to exert some degree of in vivo control of HIV replication, the precise correlates of protective immunity differentiating LTNPs from patients with progressive disease remain unknown. A greater understanding of the components and magnitude of an effective immune response to HIV is an important step toward the development of effective vaccines and immunotherapies.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Schmitz JE, Kuroda MJ, Santra S, et al.: Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 1999, 283:857–860. This paper was among the first to provide direct evidence of CD8+ lymphocyte-mediated restriction of lentiviral replication in vivo.PubMedCrossRefGoogle Scholar
  2. 2.
    Gundlach BR, Reiprich S, Sopper S, et al.: Env-independent protection induced by live, attenuated simian immunodeficiency virus vaccines. J Virol 1998, 72:7846–7851.PubMedGoogle Scholar
  3. 3.
    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.PubMedGoogle Scholar
  4. 4.
    Carrington M, Nelson GW, Martin MP, et al.: HLA and HIV-1: heterozygote advantage and B*35-Cw*04 disadvantage. Science 1999, 283:1748–1752.PubMedCrossRefGoogle Scholar
  5. 5.
    Gao X, Nelson GW, Karacki P, et al.: Effect of a single amino acid change in MHC class I molecules on the rate of progression to AIDS. N Engl J Med 1991, 344:1668–1675.CrossRefGoogle Scholar
  6. 6.
    Flores-Villanueva PO, Yunis EJ, Delgado JC, et al.: Control of HIV-1 viremia and protection from AIDS are associated with HLA-Bw4 homozygosity. Proc Natl Acad Sci U S A 2001, 98:5140–5145.PubMedCrossRefGoogle Scholar
  7. 7.
    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.PubMedCrossRefGoogle Scholar
  8. 8.
    Klein MR, Keet IP, D’Amaro J, et al.: Associations between HLA frequencies and pathogenic features of human immunodeficiency virus type 1 infection in seroconverters from the Amsterdam cohort of homosexual men. J Infect Dis 1994, 169:1244–1249.PubMedGoogle Scholar
  9. 9.
    Kaslow RA, Carrington M, Apple R, et al.: Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection [see comments]. Nat Med 1996, 2:405–411.PubMedCrossRefGoogle Scholar
  10. 10.
    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.PubMedGoogle Scholar
  11. 11.
    Hendel HS, Caillat-Zucman H, Lebuanec M, et al.: New class I and II HLA alleles strongly associated with opposite patterns of progression to AIDS. J Immunol 1999, 162:6942–6946.PubMedGoogle Scholar
  12. 12.
    Barouch DH, Kunstman J, Kuroda MJ, et al.: Eventual AIDS vaccine failure in a rhesus monkey by viral escape from cytotoxic T lymphocytes. Nature 2002, 415:335–339.PubMedCrossRefGoogle Scholar
  13. 13.
    O’Connor DH, Allen TM, Vogel TU, et al.: Acute phase cytotoxic T lymphocyte escape is a hallmark of simian immunodeficiency virus infection. Nat Med 2002, 8:493–499.PubMedCrossRefGoogle Scholar
  14. 14.
    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.PubMedCrossRefGoogle Scholar
  15. 15.
    Goulder PJ, Brander C, Tang Y, et al.: Evolution and transmission of stable CTL escape mutations in HIV infection. Nature 2001, 412:334–338.PubMedCrossRefGoogle Scholar
  16. 16.
    Nowak MA, May RM, Phillips RE, et al.: Antigenic oscillations and shifting immunodominance in HIV-1 infections [see comments]. Nature 1995, 375:606–611.PubMedCrossRefGoogle Scholar
  17. 17.
    Kelleher AD, Long EC, Holmes RL, et al.: Clustered mutations in HIV-1 gag are consistently required for escape from HLAB27-restricted cytotoxic T lymphocyte responses. J Exp Med 2001, 193:375–386.PubMedCrossRefGoogle Scholar
  18. 18.
    Kerkau T, Bacik JR, Bennink J, et al.: The human immunodeficiency virus type 1 (HIV-1) Vpu protein interferes with an early step in the biosynthesis of major histocompatibility complex (MHC) class I molecules. J Exp Med 1997, 185:1295–1305.PubMedCrossRefGoogle Scholar
  19. 19.
    Howcroft TK, Strebel K, Martin MA, Singer DS: Repression of MHC class I gene promoter activity by two-exon Tat of HIV. Science 1993, 260:1320–1322.PubMedCrossRefGoogle Scholar
  20. 20.
    Schwartz O, Marechal V, Le Gall S, et al.: Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein. Nat Med 1996, 2:338–342.PubMedCrossRefGoogle Scholar
  21. 21.
    Cohen GB, Gandhi RT, Davis DM, et al.: The selective downregulation of class I major histocompatibility complex proteins by HIV-1 protects HIV-infected cells from NK cells. Immunity 1999, 10:661–671.PubMedCrossRefGoogle Scholar
  22. 22.
    Collins KL, Chen BK, Kalams SA, et al.: HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes. Nature 1998, 391:397–401.PubMedCrossRefGoogle Scholar
  23. 23.
    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.PubMedCrossRefGoogle Scholar
  24. 24.
    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.PubMedGoogle Scholar
  25. 25.
    Klein MR, van Baalen CA, Holwerda AM, et al.: Kinetics of Gagspecific cytotoxic T lymphocyte responses during the clinical course of HIV-1 infection: a longitudinal analysis of rapid progressors and long-term asymptomatics. J Exp Med 1995, 181:1365–1372.PubMedCrossRefGoogle Scholar
  26. 26.
    Rinaldo C, Huang XL, Fan ZF, et al.: High levels of anti-human immunodeficiency virus type 1 (HIV-1) memory cytotoxic Tlymphocyte activity and low viral load are associated with lack of disease in HIV-1-infected long-term nonprogressors. J Virol 1995, 69:5838–5842.PubMedGoogle Scholar
  27. 27.
    Ogg GS, Jin X, Bonhoeffer S, et al.: Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA. Science 1998, 279:2103–2106.PubMedCrossRefGoogle Scholar
  28. 28.
    Kalams SA, Buchbinder SP, Rosenberg ES, et al.: Association between virus-specific cytotoxic T-lymphocyte and helper responses in human immunodeficiency virus type 1 infection. J Virol 1999, 73:6715–6720.PubMedGoogle Scholar
  29. 29.
    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.PubMedGoogle Scholar
  30. 30.
    Gea-Banacloche JC, Migueles SA, Martino L, et al.: Maintenance of large numbers of virus specific CD8+ T cells in HIV infected progressors and long term nonprogressors. J Immunol 2000, 165:1082–1092.PubMedGoogle Scholar
  31. 31.
    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. Using intracellular cytokine staining and panels of overlapping peptides spanning the entire HIV genome, this study represents one of the most comprehensive assessments of the total T-cell (CD4+ and CD8+) response to HIV.PubMedCrossRefGoogle Scholar
  32. 32.
    Migueles SA, Connors M: Frequency and function of HIVspecific CD8(+) T cells. Immunol Lett 2001, 79:141–150.PubMedCrossRefGoogle Scholar
  33. 33.
    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.PubMedCrossRefGoogle Scholar
  34. 34.
    van BaalenCA, Pontesilli O, Huisman RC, et al.: Human immunodeficiency virus type 1 Rev- and Tat-specific cytotoxic T lymphocyte frequencies inversely correlate with rapid progression to AIDS. J Gen Virol 1997, 78:1913–1918.PubMedGoogle Scholar
  35. 35.
    Pantaleo G, Demarest JF, Soudeyns H, et al.: Major expansion of CD8+ T cells with a predominant V beta usage during the primary immune response to HIV [see comments]. Nature 1994, 370:463–467.PubMedCrossRefGoogle Scholar
  36. 36.
    Altfeld M, Rosenberg ES, Shankarappa R, et al.: Cellular immune responses and viral diversity in individuals treated during acute and early HIV-1 infection. J Exp Med 2001, 193:169–180.PubMedCrossRefGoogle Scholar
  37. 37.
    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 [in process citation]. J Virol 2000, 74:7320–7330.PubMedCrossRefGoogle Scholar
  38. 38.
    Appay V, Nixon DF, Donahoe SM, et al.: HIV-specific CD8(+) T cells produce antiviral cytokines but are impaired in cytolytic function [In Process Citation]. J Exp Med 2000, 192:63–75.PubMedCrossRefGoogle Scholar
  39. 39.
    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. In this detailed analysis, the differentiation phenotype of virus-specific CD8+ T cells is characterized and compared during the primary and chronic phases of infection with four different viral pathogens.PubMedCrossRefGoogle Scholar
  40. 40.
    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.PubMedGoogle Scholar
  41. 41.
    Champagne P, Ogg GS, King AS, et al.: Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature 2001, 410:106–111.PubMedCrossRefGoogle Scholar
  42. 42.
    Walker C, Moody DJ, Stites DP, Levy JA: CD8+ lymphocytes can control HIV infection in vitro by suppressing virus replication. Science 1986, 234:1563–1566.PubMedCrossRefGoogle Scholar
  43. 43.
    Cocchi F, DeVico AL, Garzino-Demo A, et al.: Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells. Science 1995, 270:1811–1815.PubMedCrossRefGoogle Scholar
  44. 44.
    Kinter AL, Ostrowski M, Goletti D, et al.: HIV replication in CD4+ T cells of HIV-infected individuals is regulated by a balance between the viral suppressive effects of endogenous beta-chemokines and the viral inductive effects of other endogenous cytokines. Proc Natl Acad Sci U S A 1996, 93:14076–14081.PubMedCrossRefGoogle Scholar
  45. 45.
    Le Borgne S, Fevrier M, Callebaut C, et al.: CD8(+)-Cell antiviral factor activity is not restricted to human immunodeficiency virus (HIV)-specific T cells and can block HIV replication after initiation of reverse transcription. J Virol 2000, 74:4456–4464.CrossRefGoogle Scholar
  46. 46.
    Yang OO, Kalams SA, Trocha A, et al.: Suppression of human immunodeficiency virus type 1 replication by CD8+ cells: evidence for HLA class I-restricted triggering of cytolytic and noncytolytic mechanisms. J Virol 1997, 71:3120–3128.PubMedGoogle Scholar
  47. 47.
    Matloubian M, Concepcion RJ, Ahmed R: CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection. J Virol 1994, 68:8056–8063.PubMedGoogle Scholar
  48. 48.
    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.PubMedCrossRefGoogle Scholar
  49. 49.
    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.PubMedCrossRefGoogle Scholar
  50. 50.
    Pontesilli O, Carotenuto P, Kerkhof-Garde SR, et al.: Lymphoproliferative response to HIV type 1 p 24 in long-term survivors of HIV type 1 infection is predictive of persistent AIDS-free infection. AIDS Res Hum Retroviruses 1999, 15:973–981.PubMedCrossRefGoogle Scholar
  51. 51.
    Schwartz D, Sharma U, Busch M, et al.: Absence of recoverable infectious virus and unique immune responses in an asymptomatic HIV+ long-term survivor. AIDS Res Hum Retroviruses 1994, 10:1703–1711.PubMedCrossRefGoogle Scholar
  52. 52.
    Valentine FT, Paolino A, Saito A, Holzman RS: Lymphocyteproliferativeresponses to HIV antigens as a potential measure of immunological reconstitution in HIV disease [In Process Citation]. AIDS Res Hum Retroviruses 1998, 14(Suppl 2):S161-S166.PubMedGoogle Scholar
  53. 53.
    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.PubMedCrossRefGoogle Scholar
  54. 54.
    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.PubMedCrossRefGoogle Scholar
  55. 55.
    Rosenberg ES, Altfeld M, Poon SH, et al.: Immune control of HIV-1 after early treatment of acute infection. Nature 2000, 407:523–526.PubMedCrossRefGoogle Scholar
  56. 56.
    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.PubMedCrossRefGoogle Scholar
  57. 57.
    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.PubMedCrossRefGoogle Scholar
  58. 58.
    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.PubMedCrossRefGoogle Scholar
  59. 59.
    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.PubMedCrossRefGoogle Scholar
  60. 60.
    Douek DC, Brenchley JM, Betts MR, et al.: HIV preferentially infects HIV-specific CD4+ T cells. Nature 2002, 417:95–98.PubMedCrossRefGoogle Scholar
  61. 61.
    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 [see comments]. Nat Med 1999, 5:518–525. This is the first demonstration of the persistence of HIV gag-specific CD4+ memory cells in most subjects with active, progressive HIV-1 infection.PubMedCrossRefGoogle Scholar
  62. 62.
    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.PubMedCrossRefGoogle Scholar
  63. 63.
    Boni C, Bertoletti A, Penna A, et al.: Lamivudine treatment can restore T cell responsiveness in chronic hepatitis B. J Clin Invest 1998, 102:968–975.PubMedCrossRefGoogle Scholar
  64. 64.
    Gerlach JT, Diepolder HM, Jung MC, et al.: Recurrence of hepatitis C virus after loss of virus-specific CD4(+) T-cell response in acute hepatitis C. Gastroenterology 1999, 117:933–941.PubMedCrossRefGoogle Scholar
  65. 65.
    Oxenius A, Zinkernagel RM, Hengartner H: Comparison of activation versus induction of unresponsiveness of virus-specific CD4+ and CD8+ T cells upon acute versus persistent viral infection. Immunity 1998, 9:449–457.PubMedCrossRefGoogle Scholar
  66. 66.
    Dybul M, Mercier G, Belson M, et al.: CD40 ligand trimer and IL-12 enhance peripheral blood mononuclear cells and CD4 + T cell proliferation and production of IFN-gamma in response to p24 antigen in HIV-infected individuals: potential contribution of anergy to HIV-specific unresponsiveness. J Immunol 2000, 165:1685–1691.PubMedGoogle Scholar
  67. 67.
    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.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2002

Authors and Affiliations

  • Stephen A. Migueles
    • 1
  • Mark Connors
    • 1
  1. 1.LIR, National Institute of Allergy and Infectious Diseases, National Institutes of HealthBethesdaUSA

Personalised recommendations