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  • Review Article
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Success and failure of the cellular immune response against HIV-1

Nature Immunology volume 16, pages 563–570 (2015)Cite this article

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Abstract

The cellular immune response to HIV-1 has now been studied in extraordinary detail. A very large body of data provides the most likely reasons that the HIV-specific cellular immune response succeeds in a small number of people but fails in most. Understanding the success and failure of the HIV-specific cellular immune response has implications that extend not only to immunotherapies and vaccines for HIV-1 but also to the cellular immune response in other disease states. This Review focuses on the mechanisms that are most likely responsible for durable and potent immunologic control of HIV-1. Although we now have a detailed picture of the cellular immune responses to HIV-1, important questions remain regarding the nature of these responses and how they arise.

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Figure 1: Summary of events following antigen encounter by a memory HIV-specific CD8+ T cell.
Figure 2: Proposed differences in recognition of infected CD4+ T cells that might dictate differences in immunologic control between LTNP-ECs and progressors.
Figure 3: Differences in CD8+ T cell proliferation and lytic granule loading that lead to control or loss of control over HIV-1.
Figure 4: Requirements for vaccine-induced protection and control.

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References

  1. Migueles, S.A. & Connors, M. Long-term nonprogressive disease among untreated HIV-infected individuals: clinical implications of understanding immune control of HIV. J. Am. Med. Assoc. 304, 194–201 (2010).

    Article  CAS  Google Scholar 

  2. Speiser, D.E. et al. T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion? Nat. Rev. Immunol. 14, 768–774 (2014).

    Article  CAS  PubMed  Google Scholar 

  3. Walker, B.D. Elite control of HIV infection: implications for vaccines and treatment. Top. HIV Med. 15, 134–136 (2007).

    PubMed  Google Scholar 

  4. Pereyra, F. et al. Persistent low-level viremia in HIV-1 elite controllers and relationship to immunologic parameters. J. Infect. Dis. 200, 984–990 (2009).

    Article  PubMed  Google Scholar 

  5. Hunt, P.W. et al. Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J. Infect. Dis. 197, 126–133 (2008).

    Article  PubMed  Google Scholar 

  6. Michael, N.L. et al. Defective accessory genes in a human immunodeficiency virus type 1–infected long-term survivor lacking recoverable virus. J. Virol. 69, 4228–4236 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mariani, R. et al. High frequency of defective nef alleles in a long-term survivor with nonprogressive human immunodeficiency virus type 1 infection. J. Virol. 70, 7752–7764 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Deacon, N.J. et al. Genomic structure of an attenuated quasi species of HIV-1 from a blood transfusion donor and recipients. Science 270, 988–991 (1995).

    Article  CAS  PubMed  Google Scholar 

  9. Blankson, J.N. et al. Isolation and characterization of replication-competent human immunodeficiency virus type 1 from a subset of elite suppressors. J. Virol. 81, 2508–2518 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Miura, T. et al. Genetic characterization of human immunodeficiency virus type 1 in elite controllers: lack of gross genetic defects or common amino acid changes. J. Virol. 82, 8422–8430 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Migueles, S.A. 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. 77, 6889–6898 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lamine, A. et al. Replication-competent HIV strains infect HIV controllers despite undetectable viremia (ANRS EP36 study). AIDS 21, 1043–1045 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Julg, B. et al. Infrequent recovery of HIV from but robust exogenous infection of activated CD4(+) T cells in HIV elite controllers. Clin. Infect. Dis. 51, 233–238 (2010).

    Article  CAS  PubMed  Google Scholar 

  14. O'Connell, K.A. et al. Control of HIV-1 in elite suppressors despite ongoing replication and evolution in plasma virus. J. Virol. 84, 7018–7028 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Mens, H. et al. HIV-1 continues to replicate and evolve in patients with natural control of HIV infection. J. Virol. 84, 12971–12981 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bailey, J.R. et al. Transmission of human immunodeficiency virus type 1 from a patient who developed AIDS to an elite suppressor. J. Virol. 82, 7395–7410 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Buckheit, R.W. III et al. Host factors dictate control of viral replication in two HIV-1 controller/chronic progressor transmission pairs. Nat. Commun. 3, 716 (2012). This study was the first to demonstrate discordant outcomes in LTNP-EC–progressor transmission pairs despite infection with viruses that were fully replication competent. This supports other evidence that the LTNP-EC phenotype cannot be attributed solely to infection with replication-impaired or attenuated viruses.

    Article  PubMed  CAS  Google Scholar 

  18. Salgado, M. et al. HLA-B*57 elite suppressor and chronic progressor HIV-1 isolates replicate vigorously and cause CD4+ T cell depletion in humanized BLT mice. J. Virol. 88, 3340–3352 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Dean, M. et al. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study. Science 273, 1856–1862 (1996).

    Article  CAS  PubMed  Google Scholar 

  20. Cohen, O.J. et al. CXCR4 and CCR5 genetic polymorphisms in long-term nonprogressive human immunodeficiency virus infection: lack of association with mutations other than CCR5-Delta32. J. Virol. 72, 6215–6217 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Martin, M.P. et al. Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1. Nat. Genet. 39, 733–740 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Migueles, S.A. 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. USA 97, 2709–2714 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lambotte, O. et al. HIV controllers: a homogeneous group of HIV-1-infected patients with spontaneous control of viral replication. Clin. Infect. Dis. 41, 1053–1056 (2005).

    Article  PubMed  Google Scholar 

  24. Kloosterboer, N. et al. Natural controlled HIV infection: preserved HIV-specific immunity despite undetectable replication competent virus. Virology 339, 70–80 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Sáez-Cirión, A. et al. 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 (2007). This paper demonstrates the potent virus-suppressive capacity of CD8+ T cells from LTNP-ECs as a correlate of immune control, as it distinguishes LTNP-ECs from chronic progressors.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  26. Han, Y. et al. The role of protective HCP5 and HLA-C associated polymorphisms in the control of HIV-1 replication in a subset of elite suppressors. AIDS 22, 541–544 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Pereyra, F. et al. Genetic and immunologic heterogeneity among persons who control HIV infection in the absence of therapy. J. Infect. Dis. 197, 563–571 (2008).

    Article  PubMed  Google Scholar 

  28. Migueles, S.A. et al. Defective human immunodeficiency virus-specific CD8+ T-cell polyfunctionality, proliferation, and cytotoxicity are not restored by antiretroviral therapy. J. Virol. 83, 11876–11889 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Walker, B.D. & Yu, X.G. Unravelling the mechanisms of durable control of HIV-1. Nat. Rev. Immunol. 13, 487–498 (2013).

    Article  CAS  PubMed  Google Scholar 

  30. Kaech, S.M. & Ahmed, R. Immunology. CD8 T cells remember with a little help. Science 300, 263–265 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Iyasere, C. et al. Diminished proliferation of human immunodeficiency virus-specific CD4+ T cells is associated with diminished interleukin-2 (IL-2) production and is recovered by exogenous IL-2. J. Virol. 77, 10900–10909 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Emu, B. et al. Phenotypic, functional, and kinetic parameters associated with apparent T-cell control of human immunodeficiency virus replication in individuals with and without antiretroviral treatment. J. Virol. 79, 14169–14178 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kaufmann, D.E. et al. Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction. Nat. Immunol. 8, 1246–1254 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Potter, S.J. et al. Preserved central memory and activated effector memory CD4+ T-cell subsets in human immunodeficiency virus controllers: an ANRS EP36 study. J. Virol. 81, 13904–13915 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Tilton, J.C. et al. Changes in paracrine interleukin-2 requirement, CCR7 expression, frequency, and cytokine secretion of human immunodeficiency virus-specific CD4+ T cells are a consequence of antigen load. J. Virol. 81, 2713–2725 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Owen, R.E. et al. HIV+ elite controllers have low HIV-specific T-cell activation yet maintain strong, polyfunctional T-cell responses. AIDS 24, 1095–1105 (2010).

    Article  CAS  PubMed  Google Scholar 

  37. Ferre, A.L. et al. HIV controllers with HLA-DRB1*13 and HLA-DQB1*06 alleles have strong, polyfunctional mucosal CD4+ T-cell responses. J. Virol. 84, 11020–11029 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Soghoian, D.Z. et al. HIV-specific cytolytic CD4 T cell responses during acute HIV infection predict disease outcome. Sci. Transl. Med. 4, 123ra125 (2012).

    Article  CAS  Google Scholar 

  39. Loffredo, J.T. et al. Mamu-B*08-positive macaques control simian immunodeficiency virus replication. J. Virol. 81, 8827–8832 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yant, L.J. et al. The high-frequency major histocompatibility complex class I allele Mamu-B*17 is associated with control of simian immunodeficiency virus SIVmac239 replication. J. Virol. 80, 5074–5077 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Schmitz, J.E. et al. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 283, 857–860 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Friedrich, T.C. et al. Subdominant CD8+ T-cell responses are involved in durable control of AIDS virus replication. J. Virol. 81, 3465–3476 (2007). This study extends earlier studies in nonhuman primates showing that treatment with CD8+ T cell–depleting monoclonal antibodies abrogates immune-mediated control of SIV replication in LTNP-EC macaques.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hersperger, A.R., Migueles, S.A., Betts, M.R. & Connors, M. Qualitative features of the HIV-specific CD8+ T-cell response associated with immunologic control. Curr. Opin. HIV AIDS 6, 169–173 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Draenert, R. et al. Persistent recognition of autologous virus by high-avidity CD8 T cells in chronic, progressive human immunodeficiency virus type 1 infection. J. Virol. 78, 630–641 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Nou, E., Zhou, Y., Nou, D.D. & Blankson, J.N. Effective downregulation of HLA-A*2 and HLA-B*57 by primary human immunodeficiency virus type 1 isolates cultured from elite suppressors. J. Virol. 83, 6941–6946 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Goulder, P.J. et al. Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS. Nat. Med. 3, 212–217 (1997).

    Article  CAS  PubMed  Google Scholar 

  48. Goulder, P.J. et al. Evolution and transmission of stable CTL escape mutations in HIV infection. Nature 412, 334–338 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Kelleher, A.D. et al. Clustered mutations in HIV-1 gag are consistently required for escape from HLA-B27-restricted cytotoxic T lymphocyte responses. J. Exp. Med. 193, 375–386 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Brockman, M.A. et al. Escape and compensation from early HLA-B57-mediated cytotoxic T-lymphocyte pressure on human immunodeficiency virus type 1 Gag alter capsid interactions with cyclophilin A. J. Virol. 81, 12608–12618 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Bailey, J.R., Williams, T.M., Siliciano, R.F. & Blankson, J.N. Maintenance of viral suppression in HIV-1-infected HLA-B*57+ elite suppressors despite CTL escape mutations. J. Exp. Med. 203, 1357–1369 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Miura, T. et al. HLA-B57/B*5801 human immunodeficiency virus type 1 elite controllers select for rare gag variants associated with reduced viral replication capacity and strong cytotoxic T-lymphotye recognition. J. Virol. 83, 2743–2755 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. Miura, T. et al. HLA-associated viral mutations are common in human immunodeficiency virus type 1 elite controllers. J. Virol. 83, 3407–3412 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Deng, K. et al. Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations. Nature 517, 381–385 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Pereyra, F. et al. HIV control is mediated in part by CD8+ T-cell targeting of specific epitopes. J. Virol. 88, 12937–12948 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Migueles, S.A. et al. CD8+ T-cell cytotoxic capacity associated with human immunodeficiency virus-1 control can be mediated through various epitopes and human leukocyte antigen types. EBioMedicine 2, 46–58 (2015). This recent study suggests that epitope specificity or sequence conservation does not account for immune control in LTNP-ECs lacking protective alleles. Furthermore, the observed potent cytotoxic capacity was similar to that measured in B*27+ or B*57+ LTNP-ECs, which suggests that a common mechanism of control is operating in most LTNP-ECs regardless of HLA type.

    Article  PubMed  Google Scholar 

  57. Hamann, D. et al. Phenotypic and functional separation of memory and effector human CD8+ T cells. J. Exp. Med. 186, 1407–1418 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Sallusto, F. & Lanzavecchia, A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J. Exp. Med. 179, 1109–1118 (1994).

    Article  CAS  PubMed  Google Scholar 

  59. Champagne, P. et al. Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature 410, 106–111 (2001).

    Article  CAS  PubMed  Google Scholar 

  60. van Lier, R.A., ten Berge, I.J. & Gamadia, L.E. Human CD8(+) T-cell differentiation in response to viruses. Nat. Rev. Immunol. 3, 931–939 (2003).

    Article  CAS  PubMed  Google Scholar 

  61. Appay, V. et al. HIV-specific CD8(+) T cells produce antiviral cytokines but are impaired in cytolytic function. J. Exp. Med. 192, 63–75 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. van Baarle, D., Kostense, S., van Oers, M.H., Hamann, D. & Miedema, F. Failing immune control as a result of impaired CD8+ T-cell maturation: CD27 might provide a clue. Trends Immunol. 23, 586–591 (2002).

    Article  CAS  PubMed  Google Scholar 

  63. Day, C.L. et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443, 350–354 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. Petrovas, C. et al. PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J. Exp. Med. 203, 2281–2292 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Trautmann, L. et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat. Med. 12, 1198–1202 (2006).

    Article  CAS  PubMed  Google Scholar 

  66. Paiardini, M. et al. Loss of CD127 expression defines an expansion of effector CD8+ T cells in HIV-infected individuals. J. Immunol. 174, 2900–2909 (2005).

    Article  CAS  PubMed  Google Scholar 

  67. Lécuroux, C. et al. Both HLA-B*57 and plasma HIV RNA levels contribute to the HIV-specific CD8+ T cell response in HIV controllers. J. Virol. 88, 176–187 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Callan, M.F. et al. Direct visualization of antigen-specific CD8+ T cells during the primary immune response to Epstein-Barr virus in vivo. J. Exp. Med. 187, 1395–1402 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Faint, J.M. et al. Memory T cells constitute a subset of the human CD8+CD45RA+ pool with distinct phenotypic and migratory characteristics. J. Immunol. 167, 212–220 (2001).

    Article  CAS  PubMed  Google Scholar 

  70. Wherry, E.J. et al. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat. Immunol. 4, 225–234 (2003). This paper shows that virus-specific CD8+ T cells with preserved proliferative capacity are most efficient in mediating protective immunity. It also demonstrates interconversion of phenotypic subsets after antigen clearance.

    Article  CAS  PubMed  Google Scholar 

  71. Marzo, A.L. et al. Initial T cell frequency dictates memory CD8+ T cell lineage commitment. Nat. Immunol. 6, 793–799 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Jagannathan, P. et al. Comparisons of CD8+ T cells specific for human immunodeficiency virus, hepatitis C virus, and cytomegalovirus reveal differences in frequency, immunodominance, phenotype, and interleukin-2 responsiveness. J. Virol. 83, 2728–2742 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. 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).

    Article  CAS  PubMed  Google Scholar 

  74. Sandberg, J.K., Fast, N.M. & Nixon, D.F. Functional heterogeneity of cytokines and cytolytic effector molecules in human CD8+ T lymphocytes. J. Immunol. 167, 181–187 (2001).

    Article  CAS  PubMed  Google Scholar 

  75. Ochsenbein, A.F. et al. CD27 expression promotes long-term survival of functional effector-memory CD8+ cytotoxic T lymphocytes in HIV-infected patients. J. Exp. Med. 200, 1407–1417 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Migueles, S.A. et al. Lytic granule loading of CD8+ T cells is required for HIV-infected cell elimination associated with immune control. Immunity 29, 1009–1021 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Almeida, J.R. et al. Superior control of HIV-1 replication by CD8+ T cells is reflected by their avidity, polyfunctionality, and clonal turnover. J. Exp. Med. 204, 2473–2485 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Almeida, J.R. et al. Antigen sensitivity is a major determinant of CD8+ T-cell polyfunctionality and HIV-suppressive activity. Blood 113, 6351–6360 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Berger, C.T. et al. High-functional-avidity cytotoxic T lymphocyte responses to HLA-B-restricted Gag-derived epitopes associated with relative HIV control. J. Virol. 85, 9334–9345 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Mothe, B. et al. Definition of the viral targets of protective HIV-1-specific T cell responses. J. Transl. Med. 9, 208 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Mothe, B. et al. CTL responses of high functional avidity and broad variant cross-reactivity are associated with HIV control. PLoS One 7, e29717 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Viganò, S. et al. Rapid perturbation in viremia levels drives increases in functional avidity of HIV-specific CD8 T cells. PLoS Pathog. 9, e1003423 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Chen, H. et al. TCR clonotypes modulate the protective effect of HLA class I molecules in HIV-1 infection. Nat. Immunol. 13, 691–700 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Iglesias, M.C. et al. Escape from highly effective public CD8+ T-cell clonotypes by HIV. Blood 118, 2138–2149 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Price, D.A. et al. Public clonotype usage identifies protective Gag-specific CD8+ T cell responses in SIV infection. J. Exp. Med. 206, 923–936 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Mendoza, D. et al. HLA B*5701-positive long-term nonprogressors/elite controllers are not distinguished from progressors by the clonal composition of HIV-specific CD8+ T cells. J. Virol. 86, 4014–4018 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Betts, M.R. et al. HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood 107, 4781–4789 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Zimmerli, S.C. et al. HIV-1-specific IFN-gamma/IL-2-secreting CD8 T cells support CD4-independent proliferation of HIV-1-specific CD8 T cells. Proc. Natl. Acad. Sci. USA 102, 7239–7244 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ferre, A.L. et al. Mucosal immune responses to HIV-1 in elite controllers: a potential correlate of immune control. Blood 113, 3978–3989 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Sáez-Cirión, A. et al. Heterogeneity in HIV suppression by CD8 T cells from HIV controllers: association with Gag-specific CD8 T cell responses. J. Immunol. 182, 7828–7837 (2009).

    Article  PubMed  CAS  Google Scholar 

  91. de Quiros, J.C. et al. Resistance to replication of human immunodeficiency virus challenge in SCID-Hu mice engrafted with peripheral blood mononuclear cells of nonprogressors is mediated by CD8(+) T cells and associated with a proliferative response to p24 antigen. J. Virol. 74, 2023–2028 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Yang, H. et al. Antiviral inhibitory capacity of CD8+ T cells predicts the rate of CD4+ T-cell decline in HIV-1 infection. J. Infect. Dis. 206, 552–561 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Hersperger, A.R. et al. Perforin expression directly ex vivo by HIV-specific CD8 T-cells is a correlate of HIV elite control. PLoS Pathog. 6, e1000917 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Fellay, J. et al. A whole-genome association study of major determinants for host control of HIV-1. Science 317, 944–947 (2007). This was the first large-scale GWAS to report B*57 as a major host genetic factor associated with HIV-1 disease outcomes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Dalmasso, C. et al. Distinct genetic loci control plasma HIV-RNA and cellular HIV-DNA levels in HIV-1 infection: the ANRS Genome Wide Association 01 study. PLoS One 3, e3907 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Pereyra, F. et al. The major genetic determinants of HIV-1 control affect HLA class I peptide presentation. Science 330, 1551–1557 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Pelak, K. et al. Host determinants of HIV-1 control in African Americans. J. Infect. Dis. 201, 1141–1149 (2010).

    Article  CAS  PubMed  Google Scholar 

  98. Sáez-Cirión, A. et al. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLoS Pathog. 9, e1003211 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Lifson, J.D. et al. Role of CD8(+) lymphocytes in control of simian immunodeficiency virus infection and resistance to rechallenge after transient early antiretroviral treatment. J. Virol. 75, 10187–10199 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Haigwood, N.L. et al. Passive immune globulin therapy in the SIV/macaque model: early intervention can alter disease profile. Immunol. Lett. 51, 107–114 (1996).

    Article  CAS  PubMed  Google Scholar 

  101. Lifson, J.D. et al. Containment of simian immunodeficiency virus infection: cellular immune responses and protection from rechallenge following transient postinoculation antiretroviral treatment. J. Virol. 74, 2584–2593 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Altfeld, M. et al. Influence of HLA-B57 on clinical presentation and viral control during acute HIV-1 infection. AIDS 17, 2581–2591 (2003).

    Article  CAS  PubMed  Google Scholar 

  103. Horton, H. et al. Preservation of T cell proliferation restricted by protective HLA alleles is critical for immune control of HIV-1 infection. J. Immunol. 177, 7406–7415 (2006). Despite differences in overall magnitude, proliferating HIV-specific CD8+ T cells in both LTNP-ECs and progressors were shown to be dominantly restricted by protective HLA class I proteins.

    Article  CAS  PubMed  Google Scholar 

  104. Kaslow, R.A. et al. Polymorphisms in HLA class I genes associated with both favorable prognosis of human immunodeficiency virus (HIV) type 1 infection and positive cytotoxic T-lymphocyte responses to ALVAC-HIV recombinant canarypox vaccines. J. Virol. 75, 8681–8689 (2001). This sentinel study was the first to demonstrate the immunodominance of vaccine-induced responses restricted by HLA B57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Migueles, S.A. et al. Trivalent adenovirus type 5 HIV recombinant vaccine primes for modest cytotoxic capacity that is greatest in humans with protective HLA class I alleles. PLoS Pathog. 7, e1002002 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Miura, T. et al. Impaired replication capacity of acute/early viruses in persons who become HIV controllers. J. Virol. 84, 7581–7591 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Yue, L. et al. Transmitted virus fitness and host T cell responses collectively define divergent infection outcomes in two HIV-1 recipients. PLoS Pathog. 11, e1004565 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Buchbinder, S.P. et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet 372, 1881–1893 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Gray, G.E. et al. Safety and efficacy of the HVTN 503/Phambili study of a clade-B-based HIV-1 vaccine in South Africa: a double-blind, randomised, placebo-controlled test-of-concept phase 2b study. Lancet Infect. Dis. 11, 507–515 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Shiver, J.W. et al. Replication-incompetent adenoviral vaccine vector elicits effective anti-immunodeficiency-virus immunity. Nature 415, 331–335 (2002).

    Article  CAS  PubMed  Google Scholar 

  111. McElrath, M.J. et al. HIV-1 vaccine-induced immunity in the test-of-concept Step Study: a case-cohort analysis. Lancet 372, 1894–1905 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Tan, W.G. et al. Comparative analysis of simian immunodeficiency virus gag-specific effector and memory CD8+ T cells induced by different adenovirus vectors. J. Virol. 87, 1359–1372 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Hansen, S.G. et al. Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge. Nat. Med. 15, 293–299 (2009). References 113–116 represent the best examples of the control and clearance of highly pathogenic SIV by rhesus CMV vaccine–induced CD8+ T cell responses. These have critically important implications for the design of vaccines and immunotherapies for HIV and AIDS.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Hansen, S.G. et al. Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine. Nature 473, 523–527 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Hansen, S.G. et al. Immune clearance of highly pathogenic SIV infection. Nature 502, 100–104 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Hansen, S.G. et al. Cytomegalovirus vectors violate CD8+ T cell epitope recognition paradigms. Science 340, 1237874 (2013).

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

S.A.M. and M.C. are supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.

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  1. Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

    Stephen A Migueles & Mark Connors

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  1. Stephen A Migueles
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Correspondence to Mark Connors.

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Migueles, S., Connors, M. Success and failure of the cellular immune response against HIV-1. Nat Immunol 16, 563–570 (2015). https://doi.org/10.1038/ni.3161

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