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T cells and viral persistence: lessons from diverse infections


Persistent virus infections create specific problems for their hosts. Although the dynamics of immune responses after acute infection are well studied and very consistent, especially in mouse models, the patterns of responses noted during persistent infection are more complex and differ depending on the infection. In particular, CD8+ T cell responses differ widely in quantity and quality. In this review we examine these diverse responses and ask how they may arise; in particular, we discuss the function of antigen re-encounter and the CD4+ T cell responses to and the escape strategies of specific viruses. We focus on studies of four main human pathogens, cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus and hepatitis C virus, and their animal models.

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Figure 1: An 'antigen re-encounter' model linking T cell responses to various persistent viruses.
Figure 2: Function and phenotype of CD4+ T cells in persistent infection.
Figure 3: Relating T cell responses to escape strategies.


  1. 1

    Appay, V. et al. Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nat. Med. 8, 379–385 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Bachmann, M.F., Hunziker, L., Zinkernagel, R.M., Storni, T. & Kopf, M. Maintenance of memory CTL responses by T helper cells and CD40–CD40 ligand: antibodies provide the key. Eur. J. Immunol. 34, 317–326 (2004).

    CAS  PubMed  Google Scholar 

  3. 3

    Polic, B. et al. Hierarchical and redundant lymphocyte subset control precludes cytomegalovirus replication during latent infection. J. Exp. Med. 188, 1047–1054 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Doherty, P.C. & Christensen, J.P. Accessing complexity: the dynamics of virus-specific T cell responses. Annu. Rev. Immunol. 18, 561–592 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Kaech, S.M., Wherry, E.J. & Ahmed, R. Effector and memory T-cell differentiation: implications for vaccine development. Nat. Rev. Immunol. 2, 251–262 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Badovinac, V.P. & Harty, J.T. CD8+ T-cell homeostasis after infection: setting the 'curve'. Microbes Infect. 4, 441–447 (2002).

    CAS  PubMed  Google Scholar 

  7. 7

    van Stipdonk, M.J. et al. Dynamic programming of CD8+ T lymphocyte responses. Nat. Immunol. 4, 361–365 (2003).

    CAS  PubMed  Google Scholar 

  8. 8

    Kaech, S.M. et al. Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nat. Immunol. 4, 1191–1198 (2003).

    CAS  Google Scholar 

  9. 9

    Mongkolsapaya, J. et al. Original antigenic sin and apoptosis in the pathogenesis of dengue hemorrhagic fever. Nat. Med. 9, 921–927 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Lechner, F. et al. Analysis of successful immune responses in persons infected with hepatitis C virus. J. Exp. Med. 191, 1499–1512 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Shedlock, D.J. & Shen, H. Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science 300, 337–339 (2003).

    CAS  PubMed  Google Scholar 

  12. 12

    Khanolkar, A., Fuller, M.J. & Zajac, A.J. CD4 T cell-dependent CD8 T cell maturation. J. Immunol. 172, 2834–2844 (2004).

    CAS  PubMed  Google Scholar 

  13. 13

    Sun, J.C., Williams, M.A. & Bevan, M.J. CD4+ T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection. Nat. Immunol. 5, 927–933 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Janssen, E.M. et al. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 421, 852–856 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Homann, D., Teyton, L. & Oldstone, M.B. Differential regulation of antiviral T-cell immunity results in stable CD8+ but declining CD4+ T-cell memory. Nat. Med. 7, 913–919 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Day, C.L. et al. Ex vivo analysis of human memory CD4 T cells specific for hepatitis C virus using MHC class II tetramers. J. Clin. Invest. 112, 831–842 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Lucas, M. et al. Ex vivo phenotype and frequency of influenza virus-specific CD4 memory T cells. J. Virol. 78, 7284–7287 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Sallusto, F., Lenig, D., Forster, R., Lipp, M. & Lanzavecchia, A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708–712 (1999).

    CAS  Google Scholar 

  19. 19

    Ravkov, E.V., Myrick, C.M. & Altman, J.D. Immediate early effector functions of virus-specific CD8+CCR7+ memory cells in humans defined by HLA and CC chemokine ligand 19 tetramers. J. Immunol. 170, 2461–2468 (2003).

    CAS  PubMed  Google Scholar 

  20. 20

    Wherry, E.J. et al. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat. Immunol. 4, 225–234 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Baron, V. et al. The repertoires of circulating human CD8+ central and effector memory T cell subsets are largely distinct. Immunity 18, 193–204 (2003).

    Google Scholar 

  22. 22

    Dunne, P.J. et al. Epstein-Barr virus-specific CD8+ T cells that re-express CD45RA are apoptosis-resistant memory cells that retain replicative potential. Blood 100, 933–940 (2002).

    CAS  PubMed  Google Scholar 

  23. 23

    Dunne, P.J. et al. Quiescence and functional re-programming of Epstein-Barr virus (EBV)-specific CD8+ T cells during persistent infection Blood 106, 558–565 (2005).

    CAS  PubMed  Google Scholar 

  24. 24

    Badovinac, V.P., Porter, B.B. & Harty, J.T. Programmed contraction of CD8+ T cells after infection. Nat. Immunol. 3, 619–626 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Gillespie, G.M. et al. Functional heterogeneity and high frequencies of cytomegalovirus-specific CD8+ T lymphocytes in healthy seropositive donors. J. Virol. 74, 8140–8150 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Khan, N. et al. Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals. J. Immunol. 169, 1984–1992 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Komatsu, H. & Sierro, S.A.V.C. & Klenerman, P. Population analysis of antiviral T cell responses using MHC class I-peptide tetramers. Clin. Exp. Immunol. 134, 9–12 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Northfield, J., Lucas, M., Jones, H., Young, N.T. & Klenerman, P. Does memory improve with age? CD85j (ILT-2/LIR-1) expression on CD8 T cells correlates with 'memory inflation' in human cytomegalovirus infection. Immunol. Cell Biol. 83, 182–188 (2005).

    CAS  PubMed  Google Scholar 

  29. 29

    Khan, N. et al. Herpesvirus-specific CD8 T cell immunity in old age: cytomegalovirus impairs the response to a coresident EBV infection. J. Immunol. 173, 7481–7489 (2004).

    CAS  PubMed  Google Scholar 

  30. 30

    Kuijpers, T.W. et al. Frequencies of circulating cytolytic, CD45RA+CD27, CD8+ T lymphocytes depend on infection with CMV. J. Immunol. 170, 4342–4348 (2003).

    CAS  PubMed  Google Scholar 

  31. 31

    Karrer, U. et al. Memory inflation: continuous accumulation of antiviral CD8+ T cells over time. J. Immunol. 170, 2022–2029 (2003).

    CAS  PubMed  Google Scholar 

  32. 32

    Sierro, S., Rothkopf, R. & Klenerman, P. Evolution of diverse antiviral CD8+ T cell populations after murine cytomegalovirus infection. Eur. J. Immunol. 35, 1113–1123 (2005).

    CAS  PubMed  Google Scholar 

  33. 33

    Holtappels, R., Pahl-Seibert, M.F., Thomas, D. & Reddehase, M.J. Enrichment of immediate-early 1 (m123/pp89) peptide-specific CD8 T cells in a pulmonary CD62Llo memory-effector cell pool during latent murine cytomegalovirus infection of the lungs. J. Virol. 74, 11495–11503 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Gold, M.C. et al. Murine cytomegalovirus interference with antigen presentation has little effect on the size or the effector memory phenotype of the CD8 T cell response. J. Immunol. 172, 6944–6953 (2004).

    CAS  PubMed  Google Scholar 

  35. 35

    Callan, M.F. The evolution of antigen-specific CD8+ T cell responses after natural primary infection of humans with Epstein-Barr virus. Viral Immunol. 16, 3–16 (2003).

    CAS  PubMed  Google Scholar 

  36. 36

    Obar, J.J., Crist, S.G., Gondek, D.C. & Usherwood, E.J. Different functional capacities of latent and lytic antigen-specific CD8 T cells in murine gammaherpesvirus infection. J. Immunol. 172, 1213–1219 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Masopust, D., Vezys, V., Marzo, A.L. & Lefrancois, L. Preferential localization of effector memory cells in nonlymphoid tissue. Science 291, 2413–2417 (2001).

    CAS  Google Scholar 

  38. 38

    Wherry, E.J., Blattman, J.N., 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. 77, 4911–4927 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Wherry, E.J., Barber, D.L., Kaech, S.M., Blattman, J.N. & Ahmed, R. Antigen-independent memory CD8 T cells do not develop during chronic viral infection. Proc. Natl. Acad. Sci. USA 101, 16004–16009 (2004).

    CAS  PubMed  Google Scholar 

  40. 40

    Zhou, S., Ou, R., Huang, L., Price, G.E. & Moskophidis, D. Differential tissue-specific regulation of antiviral CD8+ T-cell immune responses during chronic viral infection. J. Virol. 78, 3578–3600 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Matloubian, M., Concepcion, R.J. & Ahmed, R. CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection. J. Virol. 68, 8056–8063 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Ou, R., Zhou, S., Huang, L. & Moskophidis, D. Critical role for α/β and γ interferons in persistence of lymphocytic choriomeningitis virus by clonal exhaustion of cytotoxic T cells. J. Virol. 75, 8407–8423 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Dittmer, U. et al. Functional impairment of CD8+ T cells by regulatory T cells during persistent retroviral infection. Immunity 20, 293–303 (2004).

    CAS  PubMed  Google Scholar 

  44. 44

    Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).

    CAS  Google Scholar 

  45. 45

    Roncador, G. et al. Analysis of FOXP3 protein expression in human CD4+CD25+ regulatory T cells at the single-cell level. Eur. J. Immunol. 35, 1681–1691 (2005).

    CAS  PubMed  Google Scholar 

  46. 46

    Rouse, B.T. & Suvas, S. Regulatory cells and infectious agents: detentes cordiale and contraire. J. Immunol. 173, 2211–2215 (2004).

    CAS  PubMed  Google Scholar 

  47. 47

    Lichterfeld, M. et al. Loss of HIV-1-specific CD8+ T cell proliferation after acute HIV-1 infection and restoration by vaccine-induced HIV-1-specific CD4+ T cells. J. Exp. Med. 200, 701–712 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Ogg, G.S. et al. Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA. Science 279, 2103–2106 (1998).

    CAS  PubMed  Google Scholar 

  49. 49

    Migueles, S.A. et al. HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nat. Immunol. 3, 1061–1068 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Zafiropoulos, A., Barnes, E., Piggott, C. & Klenerman, P. Analysis of 'driver' and 'passenger' CD8+ T-cell responses against variable viruses. Proc. R. Soc. Lond. B 271 (Suppl. 3), S53–S56 (2004).

    CAS  Google Scholar 

  51. 51

    Kiepiela, P. et al. Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA. Nature 432, 769–775 (2004).

    CAS  Google Scholar 

  52. 52

    Crowe, S.R., Miller, S.C., Shenyo, R.M. & Woodland, D.L. Vaccination with an acidic polymerase epitope of influenza virus elicits a potent antiviral T cell response but delayed clearance of an influenza virus challenge. J. Immunol. 174, 696–701 (2005).

    CAS  PubMed  Google Scholar 

  53. 53

    Shoukry, N.H. et al. Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection. J. Exp. Med. 197, 1645–1655 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Grakoui, A. et al. HCV persistence and immune evasion in the absence of memory T cell help. Science 302, 659–662 (2003).

    CAS  PubMed  Google Scholar 

  55. 55

    Lechner, F. et al. CD8+ T lymphocyte responses are induced during acute hepatitis C virus infection but are not sustained. Eur. J. Immunol. 30, 2479–2487 (2000).

    CAS  PubMed  Google Scholar 

  56. 56

    Lauer, G.M. et al. High resolution analysis of cellular immune responses in resolved and persistent hepatitis C virus infection. Gastroenterology 127, 924–936 (2004).

    CAS  PubMed  Google Scholar 

  57. 57

    Ward, S.M. et al. Virus-specific CD8+ T lymphocytes within the normal human liver. Eur. J. Immunol. 34, 1526–1531 (2004).

    CAS  PubMed  Google Scholar 

  58. 58

    Accapezzato, D. et al. Hepatic expansion of a virus-specific regulatory CD8+ T cell population in chronic hepatitis C virus infection. J. Clin. Invest. 113, 963–972 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Crispe, I.N. Hepatic T cells and liver tolerance. Nat. Rev. Immunol. 3, 51–62 (2003).

    CAS  PubMed  Google Scholar 

  60. 60

    Boettler, T. et al. T cells with a CD4+CD25+ regulatory phenotype suppress in vitro proliferation of virus-apecific CD8+ T cells during chronic hepatitis C virus infection. J. Virol. 79, 7860–7867 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Rushbrook, S.M. et al. Regulatory T cells suppress in vitro proliferation of virus-specific CD8+ T cells during persistent hepatitis C virus infection. J. Virol. 79, 7852–7859 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Sugimoto, K. et al. Suppression of HCV-specific T cells without differential hierarchy demonstrated ex vivo in persistent HCV infection. Hepatology 38, 1437–1448 (2003).

    PubMed  Google Scholar 

  63. 63

    Cabrera, R. et al. An immunomodulatory role for CD4+CD25+ regulatory T lymphocytes in hepatitis C virus infection. Hepatology 40, 1062–1071 (2004).

    CAS  PubMed  Google Scholar 

  64. 64

    Thursz, M., Yallop, R., Goldin, R., Trepo, C. & Thomas, H.C. Influence of MHC class II genotype on outcome of infection with hepatitis C virus. The HENCORE group. Hepatitis C European Network for Cooperative Research. Lancet 354, 2119–2124 (1999).

    CAS  PubMed  Google Scholar 

  65. 65

    McKiernan, S.M. et al. Distinct MHC class I and II alleles are associated with hepatitis C viral clearance, originating from a single source. Hepatology 40, 108–114 (2004).

    CAS  PubMed  Google Scholar 

  66. 66

    Amyes, E. et al. Characterization of the CD4+ T cell response to Epstein-Barr virus during primary and persistent infection. J. Exp. Med. 198, 903–911 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Sester, M. et al. Sustained high frequencies of specific CD4 T cells restricted to a single persistent virus. J. Virol. 76, 3748–3755 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Doherty, P.C. et al. Effector CD4+ and CD8+ T-cell mechanisms in the control of respiratory virus infections. Immunol. Rev. 159, 105–117 (1997).

    CAS  PubMed  Google Scholar 

  69. 69

    Gamadia, L.E. et al. Primary immune responses to human CMV: a critical role for IFN-γ-producing CD4+ T cells in protection against CMV disease. Blood 101, 2686–2692 (2003).

    CAS  PubMed  Google Scholar 

  70. 70

    Scriba, T.J. et al. HIV-1-specific CD4+ T lymphocyte turnover and activation increase upon viral rebound. J. Clin. Invest. 115, 443–450 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Younes, S.A. 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. 198, 1909–1922 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Semmo, N. et al. Preferential loss of IL-2 secreting CD4+ T cells in chronic HCV infection. Hepatology 41, 1019–1028 (2005).

    CAS  PubMed  Google Scholar 

  73. 73

    MacDonald, A.J. et al. CD4 T helper type 1 and regulatory T cells induced against the same epitopes on the core protein in hepatitis C virus-infected persons. J. Infect. Dis. 185, 720–727 (2002).

    CAS  PubMed  Google Scholar 

  74. 74

    Mattapallil, J.J. et al. Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection. Nature 434, 1093–1097 (2005).

    CAS  PubMed  Google Scholar 

  75. 75

    Alcami, A. & Koszinowski, U.H. Viral mechanisms of immune evasion. Immunol. Today 21, 447–455 (2000).

    CAS  PubMed  Google Scholar 

  76. 76

    Mocarski, E.S., Jr. Immune escape and exploitation strategies of cytomegaloviruses: impact on and imitation of the major histocompatibility system. Cell. Microbiol. 6, 707–717 (2004).

    CAS  PubMed  Google Scholar 

  77. 77

    Loewendorf, A. et al. Identification of a mouse cytomegalovirus gene selectively targeting CD86 expression on antigen-presenting cells. J. Virol. 78, 13062–13071 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Holtappels, R. et al. Cytomegalovirus misleads its host by priming of CD8 T cells specific for an epitope not presented in infected tissues. J. Exp. Med. 199, 131–136 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Gold, M.C. et al. The murine cytomegalovirus immunomodulatory gene m152 prevents recognition of infected cells by M45-specific CTL but does not alter the immunodominance of the M45-specific CD8 T cell response in vivo. J. Immunol. 169, 359–365 (2002).

    CAS  PubMed  Google Scholar 

  80. 80

    Manley, T.J. et al. Immune evasion proteins of human cytomegalovirus do not prevent a diverse CD8+ cytotoxic T-cell response in natural infection. Blood 104, 1075–1082 (2004).

    CAS  PubMed  Google Scholar 

  81. 81

    Reddehase, M.J. The immunogenicity of human and murine cytomegaloviruses. Curr. Opin. Immunol. 12, 390–396 (2000).

    CAS  PubMed  Google Scholar 

  82. 82

    Reddehase, M.J. Antigens and immunoevasins: opponents in cytomegalovirus immune surveillance. Nat. Rev. Immunol. 2, 831–844 (2002).

    CAS  PubMed  Google Scholar 

  83. 83

    Bunde, T. et al. Protection from cytomegalovirus after transplantation is correlated with immediate early 1-specific CD8 T cells. J. Exp. Med. 201, 1031–1036 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Phillips, R.E. et al. Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition. Nature 354, 453–459 (1991).

    CAS  PubMed  Google Scholar 

  85. 85

    Moore, C.B. et al. Evidence of HIV-1 adaptation to HLA-restricted immune responses at a population level. Science 296, 1439–1443 (2002).

    CAS  PubMed  Google Scholar 

  86. 86

    Leslie, A.J. et al. HIV evolution: CTL escape mutation and reversion after transmission. Nat. Med. 10, 282–289 (2004).

    CAS  Google Scholar 

  87. 87

    Leslie, A. et al. Transmission and accumulation of CTL escape variants drive negative associations between HIV polymorphisms and HLA. J. Exp. Med. 201, 891–902 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Erickson, A.L. et al. The outcome of hepatitis C virus infection is predicted by escape mutations in epitopes targeted by cytotoxic T lymphocytes. Immunity 15, 883–895 (2001).

    CAS  PubMed  Google Scholar 

  89. 89

    Timm, J. et al. CD8 epitope escape and reversion in acute HCV infection. J. Exp. Med. 200, 1593–1604 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Cox, A.L. et al. Cellular immune selection with hepatitis C virus persistence in humans. J. Exp. Med. 201, 1741–1752 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Ray, S.C. et al. Divergent and convergent evolution after a common-source outbreak of hepatitis C virus. J. Exp. Med. 201, 1753–1759 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Komatsu, H. et al. Do antiviral CD8+ T cells select hepatitis C virus escape mutants? Analysis in diverse epitopes targeted by human intrahepatic CD8+ T lymphocytes. J. Viral Hepat. (in the press; 10.1111./j1365–2893.2005.00676.x).

  93. 93

    Collins, K.L., Chen, B.K., Kalams, S.A., Walker, B.D. & Baltimore, D. HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes. Nature 391, 397–401 (1998).

    CAS  PubMed  Google Scholar 

  94. 94

    Swigut, T. et al. Impact of Nef-mediated downregulation of major histocompatibility complex class I on immune response to simian immunodeficiency virus. J. Virol. 78, 13335–13344 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Learmont, J.C. et al. Immunologic and virologic status after 14 to 18 years of infection with an attenuated strain of HIV-1. A report from the Sydney Blood Bank Cohort. N. Engl. J. Med. 340, 1715–1722 (1999).

    CAS  PubMed  Google Scholar 

  96. 96

    Ciurea, A., Hunziker, L., Klenerman, P., Hengartner, H. & Zinkernagel, R.M. Impairment of CD4+ T cell responses during chronic virus infection prevents neutralizing antibody responses against virus escape mutants. J. Exp. Med. 193, 297–305 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Zinkernagel, R.M. Immunology taught by viruses. Science 271, 173–178 (1996).

    CAS  PubMed  Google Scholar 

  98. 98

    Hoji, A. & Rinaldo, C.R. Human CD8+ T cells specific for influenza A virus M1 display broad expression of maturation-associated phenotypic markers and chemokine receptors. Immunology 115, 239–245 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

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We thank S. Sierro, P. Goulder, N. Semmo, K. Cho and S. Ward for comments. Supported by the Wellcome trust, the European Union (VIRGIL network), the James Martin School of the 21st Century, Oxford, and the National Institutes of Health (AI47206).

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Klenerman, P., Hill, A. T cells and viral persistence: lessons from diverse infections. Nat Immunol 6, 873–879 (2005).

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