Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

CD8+ T cells in HIV control, cure and prevention

Abstract

HIV infection can be effectively treated by lifelong administration of combination antiretroviral therapy, but an effective vaccine will likely be required to end the HIV epidemic. Although the majority of current vaccine strategies focus on the induction of neutralizing antibodies, there is substantial evidence that cellular immunity mediated by CD8+ T cells can sustain long-term disease-free and transmission-free HIV control and may be harnessed to induce both therapeutic and preventive antiviral effects. In this Review, we discuss the increasing evidence derived from individuals who spontaneously control infection without antiretroviral therapy as well as preclinical immunization studies that provide a clear rationale for renewed efforts to develop a CD8+ T cell-based HIV vaccine in conjunction with B cell vaccine efforts. Further, we outline the remaining challenges in translating these findings into viable HIV prevention, treatment and cure strategies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Ex vivo CD8+ T cell function and phenotype are modulated by the magnitude and duration of in vivo HIV antigen exposure.
Fig. 2: CD8+ T cell function and specificity differentiate HIV controllers and progressors.
Fig. 3: HIV-specific CD8+ T cell responses in natural infection as well as following therapeutic and preventive vaccination.

Similar content being viewed by others

References

  1. Eisinger, R. W., Dieffenbach, C. W. & Fauci, A. S. HIV viral load and transmissibility of HIV infection: undetectable equals untransmittable. JAMA 321, 451–452 (2019).

    PubMed  Google Scholar 

  2. Katz, I. T., Ehrenkranz, P. & El-Sadr, W. The global HIV epidemic: what will it take to get to the finish line? JAMA 319, 1094–1095 (2018).

    PubMed  Google Scholar 

  3. Siliciano, J. D. & Siliciano, R. F. Recent developments in the effort to cure HIV infection: going beyond N = 1. J. Clin. Invest. 126, 409–414 (2016).

    PubMed  PubMed Central  Google Scholar 

  4. Korber, B. et al. Evolutionary and immunological implications of contemporary HIV-1 variation. Br. Med. Bull. 58, 19–42 (2001).

    CAS  PubMed  Google Scholar 

  5. Pitisuttithum, P. et al. Randomized, double-blind, placebo-controlled efficacy trial of a bivalent recombinant glycoprotein 120 HIV-1 vaccine among injection drug users in Bangkok, Thailand. J. Infect. Dis. 194, 1661–1671 (2006).

    CAS  PubMed  Google Scholar 

  6. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Rerks-Ngarm, S. et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N. Engl. J. Med. 361, 2209–2220 (2009).

    CAS  PubMed  Google Scholar 

  8. Hutter, G. et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N. Engl. J. Med. 360, 692–698 (2009).

    PubMed  Google Scholar 

  9. Gupta, R. K. et al. HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-cell transplantation. Nature 568, 244–248 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Yang, O. O., Cumberland, W. G., Escobar, R., Liao, D. & Chew, K. W. Demographics and natural history of HIV-1-infected spontaneous controllers of viremia. AIDS 31, 1091–1098 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Mehandru, S. et al. Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract. J. Exp. Med. 200, 761–770 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Salazar-Gonzalez, J. F. et al. Genetic identity, biological phenotype, and evolutionary pathways of transmitted/founder viruses in acute and early HIV-1 infection. J. Exp. Med. 206, 1273–1289 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 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).

    CAS  PubMed  Google Scholar 

  14. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 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).

    CAS  PubMed  Google Scholar 

  16. O’Brien, T. R. et al. Serum HIV-1 RNA levels and time to development of AIDS in the multicenter hemophilia cohort study. JAMA 276, 105–110 (1996).

    PubMed  Google Scholar 

  17. Quinn, T. C. et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N. Engl. J. Med. 342, 921–929 (2000).

    CAS  PubMed  Google Scholar 

  18. Gray, R. H. et al. Probability of HIV-1 transmission per coital act in monogamous, heterosexual, HIV-1-discordant couples in Rakai, Uganda. Lancet 357, 1149–1153 (2001).

    CAS  PubMed  Google Scholar 

  19. Gurdasani, D. et al. A systematic review of definitions of extreme phenotypes of HIV control and progression. AIDS 28, 149–162 (2014).

    PubMed  Google Scholar 

  20. Kaslow, R. A. et al. Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection. Nat. Med. 2, 405–411 (1996).

    CAS  PubMed  Google Scholar 

  21. 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).

    CAS  PubMed  Google Scholar 

  22. Pereyra, F. et al. The major genetic determinants of HIV-1 control affect HLA class I peptide presentation. Science 330, 1551–1557 (2010). Genome-wide association study of thousands of individuals confirmed that polymorphisms within the HLA class I binding pocket are strongly associated with spontaneous HIV control.

    PubMed  PubMed Central  Google Scholar 

  23. Fellay, J. et al. A whole-genome association study of major determinants for host control of HIV-1. Science 317, 944–947 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 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).

    PubMed  PubMed Central  Google Scholar 

  25. Limou, S. et al. Genomewide association study of an AIDS-nonprogression cohort emphasizes the role played by HLA genes (ANRS Genomewide Association Study 02). J. Infect. Dis. 199, 419–426 (2009).

    PubMed  Google Scholar 

  26. McLaren, P. J. et al. Evaluating the impact of functional genetic variation on HIV-1 control. J. Infect. Dis. 216, 1063–1069 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  28. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Chowdhury, A. et al. Differential impact of in vivo CD8+ T lymphocyte depletion in controller versus progressor simian immunodeficiency virus-infected macaques. J. Virol. 89, 8677–8686 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Dalod, M. 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. 73, 7108–7116 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Gea-Banacloche, J. C. et al. Maintenance of large numbers of virus-specific CD8+ T cells in HIV-infected progressors and long-term nonprogressors. J. Immunol. 165, 1082–1092 (2000).

    CAS  PubMed  Google Scholar 

  33. Betts, M. R. 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. 75, 11983–11991 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Migueles, S. A. & Connors, M. Frequency and function of HIV-specific CD8+ T cells. Immunol. Lett. 79, 141–150 (2001).

    CAS  PubMed  Google Scholar 

  35. Addo, M. M. 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. 77, 2081–2092 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Varadarajan, N. et al. A high-throughput single-cell analysis of human CD8+ T cell functions reveals discordance for cytokine secretion and cytolysis. J. Clin. Invest. 121, 4322–4331 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Saez-Cirion, 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).

    CAS  PubMed  Google Scholar 

  39. 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).

    PubMed  PubMed Central  Google Scholar 

  40. Lecuroux, 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).

    PubMed  PubMed Central  Google Scholar 

  41. Noel, N. et al. Long-term spontaneous control of HIV-1 is related to low frequency of infected cells and inefficient viral reactivation. J. Virol. 90, 6148–6158 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 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). Maintenance of HIV-specific CD8 + T cell proliferation upon antigenic stimulation strongly differentiated spontaneous controllers from non-controllers and was associated with expression of the cytolytic effector perforin.

    CAS  PubMed  Google Scholar 

  43. 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). Cytolytic function of HIV-specific CD8 + T cells was enhanced in spontaneous controllers upon antigenic stimulation and expansion compared with non-escaped responses in non-controllers.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Ndhlovu, Z. M. et al. The breadth of expandable memory CD8+ T cells inversely correlates with residual viral loads in HIV elite controllers. J. Virol. 89, 10735–10747 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Gaiha, G. D. et al. Dysfunctional HIV-specific CD8+ T cell proliferation is associated with increased caspase-8 activity and mediated by necroptosis. Immunity 41, 1001–1012 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Rehr, M. et al. Emergence of polyfunctional CD8+ T cells after prolonged suppression of human immunodeficiency virus replication by antiretroviral therapy. J. Virol. 82, 3391–3404 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Shasha, D. et al. Elite controller CD8+ T cells exhibit comparable viral inhibition capacity, but better sustained effector properties compared to chronic progressors. J. Leukoc. Biol. 100, 1425–1433 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Yang, O. O. et al. Efficient lysis of human immunodeficiency virus type 1-infected cells by cytotoxic T lymphocytes. J. Virol. 70, 5799–5806 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Sacha, J. B. et al. Gag-specific CD8+ T lymphocytes recognize infected cells before AIDS-virus integration and viral protein expression. J. Immunol. 178, 2746–2754 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Monel, B. et al. HIV controllers exhibit effective CD8+ T cell recognition of HIV-1-infected non-activated CD4+ T cells. Cell Rep. 27, 142–153.e4 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Marsh, S. G. E., Parham, P. & Barber, L. D. The HLA FactsBook (Academic Press, 2000).

  53. Kiepiela, P. et al. CD8+ T-cell responses to different HIV proteins have discordant associations with viral load. Nat. Med. 13, 46–53 (2007).

    CAS  PubMed  Google Scholar 

  54. Zuniga, R. et al. Relative dominance of Gag p24-specific cytotoxic T lymphocytes is associated with human immunodeficiency virus control. J. Virol. 80, 3122–3125 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Edwards, B. H. et al. Magnitude of functional CD8+ T-cell responses to the gag protein of human immunodeficiency virus type 1 correlates inversely with viral load in plasma. J. Virol. 76, 2298–2305 (2002).

    CAS  PubMed  PubMed Central  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 (2014).

    PubMed  PubMed Central  Google Scholar 

  57. Rolland, M. et al. HIV-1 conserved-element vaccines: relationship between sequence conservation and replicative capacity. J. Virol. 87, 5461–5467 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Dahirel, V. et al. Coordinate linkage of HIV evolution reveals regions of immunological vulnerability. Proc. Natl Acad. Sci. USA 108, 11530–11535 (2011).

    CAS  PubMed  Google Scholar 

  59. Ferguson, A. L. et al. Translating HIV sequences into quantitative fitness landscapes predicts viral vulnerabilities for rational immunogen design. Immunity 38, 606–617 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Barton, J. P. et al. Relative rate and location of intra-host HIV evolution to evade cellular immunity are predictable. Nat. Commun. 7, 11660 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Gaiha, G. D. et al. Structural topology defines protective CD8+ T cell epitopes in the HIV proteome. Science 364, 480–484 (2019). Network analysis of HIV protein structures identified CD8 + T cell epitopes derived from topologically important regions of the viral proteome that were constrained from mutation, targeted by proliferative responses in spontaneous HIV controllers and presented by common HLA alleles with broad representation in the global population.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Kosmrlj, A. et al. Effects of thymic selection of the T-cell repertoire on HLA class I-associated control of HIV infection. Nature 465, 350–354 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Flerin, N. C. et al. T-cell receptor (TCR) clonotype-specific differences in inhibitory activity of HIV-1 cytotoxic T-cell clones is not mediated by TCR alone. J. Virol. 91, e02412–16 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Joglekar, A. V. et al. T cell receptors for the HIV KK10 epitope from patients with differential immunologic control are functionally indistinguishable. Proc. Natl Acad. Sci. USA 115, 1877–1882 (2018).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Gorin, A. M. et al. HIV-1 epitopes presented by MHC class I types associated with superior immune containment of viremia have highly constrained fitness landscapes. PLoS Pathog. 13, e1006541 (2017). Saturation mutagenesis of immunodominant CD8 + T cell epitopes revealed that those presented by protective HLA alleles (B*57, B*27) tolerated markedly fewer single and double mutations, implicating epitope mutational constraint as a contributing factor to HLA-mediated control of HIV.

    PubMed  PubMed Central  Google Scholar 

  71. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. O’Connell, K. A. et al. Prolonged control of an HIV type 1 escape variant following treatment interruption in an HLA-B*27-positive patient. AIDS Res. Hum. Retroviruses 26, 1307–1311 (2010).

    PubMed  PubMed Central  Google Scholar 

  73. Pohlmeyer, C. W., Buckheit, R. W. 3rd, Siliciano, R. F. & Blankson, J. N. CD8+ T cells from HLA-B*57 elite suppressors effectively suppress replication of HIV-1 escape mutants. Retrovirology 10, 152 (2013).

    PubMed  PubMed Central  Google Scholar 

  74. McMichael, A. J. & Carrington, M. Topological perspective on HIV escape. Science 364, 438–439 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Brenchley, J. M. et al. CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J. Exp. Med. 200, 749–759 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Perreau, M. et al. Follicular helper T cells serve as the major CD4 T cell compartment for HIV-1 infection, replication, and production. J. Exp. Med. 210, 143–156 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Banga, R. et al. PD-1+ and follicular helper T cells are responsible for persistent HIV-1 transcription in treated aviremic individuals. Nat. Med. 22, 754–761 (2016).

    CAS  PubMed  Google Scholar 

  79. Connick, E. et al. CTL fail to accumulate at sites of HIV-1 replication in lymphoid tissue. J. Immunol. 178, 6975–6983 (2007).

    CAS  PubMed  Google Scholar 

  80. Quigley, M. F., Gonzalez, V. D., Granath, A., Andersson, J. & Sandberg, J. K. CXCR5+ CCR7- CD8 T cells are early effector memory cells that infiltrate tonsil B cell follicles. Eur. J. Immunol. 37, 3352–3362 (2007).

    CAS  PubMed  Google Scholar 

  81. Connick, E. et al. Compartmentalization of simian immunodeficiency virus replication within secondary lymphoid tissues of rhesus macaques is linked to disease stage and inversely related to localization of virus-specific CTL. J. Immunol. 193, 5613–5625 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Petrovas, C. et al. Follicular CD8 T cells accumulate in HIV infection and can kill infected cells in vitro via bispecific antibodies. Sci. Transl Med. 9, eaag2285 (2017).

    PubMed  PubMed Central  Google Scholar 

  83. Leong, Y. A. et al. CXCR5+ follicular cytotoxic T cells control viral infection in B cell follicles. Nat. Immunol. 17, 1187–1196 (2016).

    CAS  PubMed  Google Scholar 

  84. He, R. et al. Follicular CXCR5-expressing CD8+ T cells curtail chronic viral infection. Nature 537, 412–428 (2016).

    CAS  PubMed  Google Scholar 

  85. Mylvaganam, G. H. et al. Dynamics of SIV-specific CXCR5+ CD8 T cells during chronic SIV infection. Proc. Natl Acad. Sci. USA 114, 1976–1981 (2017).

    CAS  PubMed  Google Scholar 

  86. Li, S. et al. Simian immunodeficiency virus-producing cells in follicles are partially suppressed by CD8+ cells in vivo. J. Virol. 90, 11168–11180 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Fukazawa, Y. et al. B cell follicle sanctuary permits persistent productive simian immunodeficiency virus infection in elite controllers. Nat. Med. 21, 132–139 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Boritz, E. A. et al. Multiple origins of virus persistence during natural control of HIV infection. Cell 166, 1004–1015 (2016). Sequencing of HIV genomes, integration sites and T cell receptors revealed active HIV replication in lymph nodes of spontaneous HIV controllers despite undetectable viraemia, suggesting ongoing viral replication within lymphoid sanctuaries.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Mueller, S. N. & Mackay, L. K. Tissue-resident memory T cells: local specialists in immune defence. Nat. Rev. Immunol. 16, 79–89 (2016).

    CAS  PubMed  Google Scholar 

  90. Reuter, M. A. et al. HIV-specific CD8+ T cells exhibit reduced and differentially regulated cytolytic activity in lymphoid tissue. Cell Rep. 21, 3458–3470 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Buggert, M. et al. Identification and characterization of HIV-specific resident memory CD8+ T cells in human lymphoid tissue. Sci. Immunol. 3, eaar4526 (2018). HIV-specific CD8 + T cells in lymphoid tissue of spontaneous controllers resembled tissue-resident memory cells, exhibited skewed TCR clonotypes and expressed more effector genes compared with circulating CD8 + T cells.

    PubMed  PubMed Central  Google Scholar 

  92. Nguyen, S. et al. Elite control of HIV is associated with distinct functional and transcriptional signatures in lymphoid tissue CD8+ T cells. Sci. Transl Med. 11, eaax4077 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Martin, M. P. et al. Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS. Nat. Genet. 31, 429–434 (2002).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Pelak, K. et al. Copy number variation of KIR genes influences HIV-1 control. PLoS Biol. 9, e1001208 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Apps, R. et al. Influence of HLA-C expression level on HIV control. Science 340, 87–91 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Ramsuran, V. et al. Elevated HLA-A expression impairs HIV control through inhibition of NKG2A-expressing cells. Science 359, 86–90 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Veenhuis, R. T. et al. Long-term remission despite clonal expansion of replication-competent HIV-1 isolates. JCI Insight 3, 122795 (2018).

    PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Casado, C. et al. Viral characteristics associated with the clinical nonprogressor phenotype are inherited by viruses from a cluster of HIV-1 elite controllers. mBio 9, e02338–17 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Zaunders, J. et al. Possible clearance of transfusion-acquired nef/LTR-deleted attenuated HIV-1 infection by an elite controller with CCR5 Δ32 heterozygous and HLA-B57 genotype. J. Virus Erad. 5, 73–83 (2019).

    PubMed  PubMed Central  Google Scholar 

  103. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Buckheit, R. W. 3rd et al. Host factors dictate control of viral replication in two HIV-1 controller/chronic progressor transmission pairs. Nat. Commun. 3, 716 (2012).

    PubMed  PubMed Central  Google Scholar 

  105. 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).

    PubMed  PubMed Central  Google Scholar 

  106. Carlson, J. M. et al. Impact of pre-adapted HIV transmission. Nat. Med. 22, 606–613 (2016).

    PubMed  PubMed Central  Google Scholar 

  107. Bailey, J. R. et al. Neutralizing antibodies do not mediate suppression of human immunodeficiency virus type 1 in elite suppressors or selection of plasma virus variants in patients on highly active antiretroviral therapy. J. Virol. 80, 4758–4770 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Lambotte, O. et al. Heterogeneous neutralizing antibody and antibody-dependent cell cytotoxicity responses in HIV-1 elite controllers. AIDS 23, 897–906 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 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).

    PubMed  PubMed Central  Google Scholar 

  110. Doria-Rose, N. A. et al. Breadth of human immunodeficiency virus-specific neutralizing activity in sera: clustering analysis and association with clinical variables. J. Virol. 84, 1631–1636 (2010).

    CAS  PubMed  Google Scholar 

  111. Freund, N. T. et al. Coexistence of potent HIV-1 broadly neutralizing antibodies and antibody-sensitive viruses in a viremic controller. Sci. Transl Med. 9, eaal2144 (2017).

    PubMed  PubMed Central  Google Scholar 

  112. Ackerman, M. E. et al. Polyfunctional HIV-specific antibody responses are associated with spontaneous HIV control. PLoS Pathog. 12, e1005315 (2016).

    PubMed  PubMed Central  Google Scholar 

  113. Smalls-Mantey, A. et al. Antibody-dependent cellular cytotoxicity against primary HIV-infected CD4+ T cells is directly associated with the magnitude of surface IgG binding. J. Virol. 86, 8672–8680 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Mudd, P. A. et al. Reduction of CD4+ T cells in vivo does not affect virus load in macaque elite controllers. J. Virol. 85, 7454–7459 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Schmitz, J. E. et al. Effect of humoral immune responses on controlling viremia during primary infection of rhesus monkeys with simian immunodeficiency virus. J. Virol. 77, 2165–2173 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Pollack, R. A. et al. Defective HIV-1 proviruses are expressed and can be recognized by cytotoxic T lymphocytes, which shape the proviral landscape. Cell Host Microbe 21, 494–506.e4 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. de Azevedo, S. S. D. et al. Highly divergent patterns of genetic diversity and evolution in proviral quasispecies from HIV controllers. Retrovirology 14, 29 (2017).

    PubMed  PubMed Central  Google Scholar 

  118. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Li, J. Z. et al. ART reduces T cell activation and immune exhaustion markers in HIV controllers. Clin. Infect. Dis. https://doi.org/10.1093/cid/ciz442 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  120. 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).

    CAS  PubMed  Google Scholar 

  121. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Graf, E. H. et al. Elite suppressors harbor low levels of integrated HIV DNA and high levels of 2-LTR circular HIV DNA compared to HIV+ patients on and off HAART. PLoS Pathog. 7, e1001300 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Hatano, H. et al. Comparison of HIV DNA and RNA in gut-associated lymphoid tissue of HIV-infected controllers and noncontrollers. AIDS 27, 2255–2260 (2013).

    PubMed  PubMed Central  Google Scholar 

  124. Mendoza, D. et al. Comprehensive analysis of unique cases with extraordinary control over HIV replication. Blood 119, 4645–4655 (2012). Characterization of individuals with extraordinary CD8 + T cell-mediated spontaneous control of HIV infection to levels at which replication-competent virus was unable to be recovered, suggesting potential avenues for functional cure, remission or perhaps even clearance of replication-competent HIV reservoirs.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Saez-Cirion, 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Namazi, G. et al. The Control of HIV after Antiretroviral Medication Pause (CHAMP) study: posttreatment controllers identified from 14 clinical studies. J. Infect. Dis. 218, 1954–1963 (2018).

    PubMed  PubMed Central  Google Scholar 

  127. Williams, J. P. et al. HIV-1 DNA predicts disease progression and post-treatment virological control. eLife 3, e03821 (2014).

    PubMed  PubMed Central  Google Scholar 

  128. Lodi, S. et al. Immunovirologic control 24 months after interruption of antiretroviral therapy initiated close to HIV seroconversion. Arch. Intern. Med. 172, 1252–1255 (2012).

    PubMed  Google Scholar 

  129. Goujard, C. et al. HIV-1 control after transient antiretroviral treatment initiated in primary infection: role of patient characteristics and effect of therapy. Antivir. Ther. 17, 1001–1009 (2012).

    CAS  PubMed  Google Scholar 

  130. Sharaf, R. et al. HIV-1 proviral landscapes distinguish posttreatment controllers from noncontrollers. J. Clin. Invest. 128, 4074–4085 (2018).

    PubMed  PubMed Central  Google Scholar 

  131. Park, Y. J. et al. Impact of HLA class I alleles on timing of HIV rebound after antiretroviral treatment interruption. Pathog. Immun. 2, 431–445 (2017).

    PubMed  PubMed Central  Google Scholar 

  132. Briney, B. et al. Tailored immunogens direct affinity maturation toward HIV neutralizing antibodies. Cell 166, 1459–1470.e11 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Escolano, A. et al. Sequential immunization elicits broadly neutralizing anti-HIV-1 antibodies in Ig knockin mice. Cell 166, 1445–1458.e12 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Steichen, J. M. et al. A generalized HIV vaccine design strategy for priming of broadly neutralizing antibody responses. Science 366, eaax4380 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Kolodkin-Gal, D. et al. Efficiency of cell-free and cell-associated virus in mucosal transmission of human immunodeficiency virus type 1 and simian immunodeficiency virus. J. Virol. 87, 13589–13597 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Parsons, M. S. et al. Partial efficacy of a broadly neutralizing antibody against cell-associated SHIV infection. Sci. Transl Med. 9, eaaf1483 (2017).

    PubMed  Google Scholar 

  137. Abela, I. A. et al. Cell-cell transmission enables HIV-1 to evade inhibition by potent CD4bs directed antibodies. PLoS Pathog. 8, e1002634 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Buckheit, R. W. III, Siliciano, R. F. & Blankson, J. N. Primary CD8+ T cells from elite suppressors effectively eliminate non-productively HIV-1 infected resting and activated CD4+ T cells. Retrovirology 10, 68 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Hammer, S. M. et al. Efficacy trial of a DNA/rAd5 HIV-1 preventive vaccine. N. Engl. J. Med. 369, 2083–2092 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Rolland, M. et al. Genetic impact of vaccination on breakthrough HIV-1 sequences from the STEP trial. Nat. Med. 17, 366–371 (2011). HIV sequence analysis of breakthrough infections from 68 participants of the STEP trial revealed a ‘sieving’ effect at commonly targeted immunodominant epitopes, suggesting emergence of viral escape from vaccine-induced CD8 + T cell responses.

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Janes, H. E. et al. Higher T-cell responses induced by DNA/rAd5 HIV-1 preventive vaccine are associated with lower HIV-1 infection risk in an efficacy trial. J. Infect. Dis. 215, 1376–1385 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Mudd, P. A. et al. Vaccine-induced CD8+ T cells control AIDS virus replication. Nature 491, 129–133 (2012). Vaccine-induced CD8 + T cell epitopes directed towards specific epitopes achieved durable viral control after challenge in six of eight animals, providing proof of principle that narrowly targeted vaccine-induced CD8 + T cell responses can control viral replication.

    CAS  PubMed  Google Scholar 

  143. Letourneau, S. et al. Design and pre-clinical evaluation of a universal HIV-1 vaccine. PLoS One 2, e984 (2007).

    PubMed  PubMed Central  Google Scholar 

  144. Rolland, M., Nickle, D. C. & Mullins, J. I. HIV-1 group M conserved elements vaccine. PLoS Pathog. 3, e157 (2007).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Kallas, E. G. et al. Antigenic competition in CD4+ T cell responses in a randomized, multicenter, double-blind clinical HIV vaccine trial. Sci. Transl Med. 11, eaaw1673 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Chamcha, V. et al. Strong TH1-biased CD4 T cell responses are associated with diminished SIV vaccine efficacy. Sci. Transl Med. 11, eaav1800 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Santra, S. et al. Mosaic vaccines elicit CD8+ T lymphocyte responses that confer enhanced immune coverage of diverse HIV strains in monkeys. Nat. Med. 16, 324–328 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Barouch, D. H. et al. Mosaic HIV-1 vaccines expand the breadth and depth of cellular immune responses in rhesus monkeys. Nat. Med. 16, 319–323 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Barouch, D. H. et al. Evaluation of a mosaic HIV-1 vaccine in a multicentre, randomised, double-blind, placebo-controlled, phase 1/2a clinical trial (APPROACH) and in rhesus monkeys (NHP 13-19). Lancet 392, 232–243 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Ondondo, B. et al. Novel conserved-region T-cell mosaic vaccine with high global HIV-1 coverage is recognized by protective responses in untreated infection. Mol. Ther. 24, 832–842 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Kim, J., Kim, A. R. & Shin, E. C. Cytomegalovirus infection and memory T cell inflation. Immune Netw. 15, 186–190 (2015).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Hansen, S. G. et al. Immune clearance of highly pathogenic SIV infection. Nature 502, 100–104 (2013). Progressive clearance of SIV from ~50% of RhCMV-vectored SIV-vaccinated rhesus macaques suggests that vaccine-induced effector-memory CD8 + T cells are capable of preventing the establishment of persistent viral reservoirs.

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Hansen, S. G. et al. A live-attenuated RhCMV/SIV vaccine shows long-term efficacy against heterologous SIV challenge. Sci. Transl Med. 11, eaaw2607 (2019).

    PubMed  PubMed Central  Google Scholar 

  157. Hansen, S. G. et al. Broadly targeted CD8+ T cell responses restricted by major histocompatibility complex E. Science 351, 714–720 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Geraghty, D. E., Stockschleader, M., Ishitani, A. & Hansen, J. A. Polymorphism at the HLA-E locus predates most HLA-A and -B polymorphism. Hum. Immunol. 33, 174–184 (1992).

    CAS  PubMed  Google Scholar 

  159. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Mylvaganam, G., Yanez, A. G., Maus, M. & Walker, B. D. Toward T cell-mediated control or elimination of HIV reservoirs: lessons from cancer immunology. Front. Immunol. 10, 2109 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Amancha, P. K., Hong, J. J., Rogers, K., Ansari, A. A. & Villinger, F. In vivo blockade of the programmed cell death-1 pathway using soluble recombinant PD-1-Fc enhances CD4+ and CD8+ T cell responses but has limited clinical benefit. J. Immunol. 191, 6060–6070 (2013).

    CAS  PubMed  Google Scholar 

  162. Mylvaganam, G. H. et al. Combination anti-PD-1 and antiretroviral therapy provides therapeutic benefit against SIV. JCI Insight 3, 122940 (2018).

    PubMed  Google Scholar 

  163. Bekerman, E. et al. PD-1 blockade and TLR7 activation lack therapeutic benefit in chronic simian immunodeficiency virus-infected macaques on antiretroviral therapy. Antimicrob. Agents Chemother. 63, e01163–19 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Lu, W., Arraes, L. C., Ferreira, W. T. & Andrieu, J. M. Therapeutic dendritic-cell vaccine for chronic HIV-1 infection. Nat. Med. 10, 1359–1365 (2004).

    CAS  PubMed  Google Scholar 

  165. Kloverpris, H. et al. Induction of novel CD8+ T-cell responses during chronic untreated HIV-1 infection by immunization with subdominant cytotoxic T-lymphocyte epitopes. AIDS 23, 1329–1340 (2009).

    CAS  PubMed  Google Scholar 

  166. Garcia, F. et al. A dendritic cell-based vaccine elicits T cell responses associated with control of HIV-1 replication. Sci. Transl Med. 5, 166ra2 (2013).

    PubMed  Google Scholar 

  167. Levy, Y. et al. Dendritic cell-based therapeutic vaccine elicits polyfunctional HIV-specific T-cell immunity associated with control of viral load. Eur. J. Immunol. 44, 2802–2810 (2014).

    CAS  PubMed  Google Scholar 

  168. Macatangay, B. J. et al. Therapeutic vaccination with dendritic cells loaded with autologous HIV type 1-infected apoptotic cells. J. Infect. Dis. 213, 1400–1409 (2016).

    CAS  PubMed  Google Scholar 

  169. Borducchi, E. N. et al. Ad26/MVA therapeutic vaccination with TLR7 stimulation in SIV-infected rhesus monkeys. Nature 540, 284–287 (2016). rAd26 and modified vaccinia Ankara-vectored SIV therapeutic vaccine with TLR7 agonist induced broad CD8 + T cell responses, delayed viral rebound following ART interruption and reduced set point viral loads in immunized rhesus macaques.

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Mothe, B. et al. Therapeutic vaccination refocuses T-cell responses towards conserved regions of HIV-1 in early treated individuals (BCN 01 study). EClinicalMedicine 11, 65–80 (2019). Immunogenicity trial of conserved HIV elements vectored by ChAdV and modified vaccinia Ankara in therapeutic vaccine setting elicited strong responses against vaccine epitopes that would otherwise be subdominant in natural infection, providing proof of principle that CD8 + T cell responses in chronically infected individuals can be redirected towards specific regions of the viral proteome.

    PubMed  PubMed Central  Google Scholar 

  171. Shapiro, S. Z. Lessons for general vaccinology research from attempts to develop an HIV vaccine. Vaccine 37, 3400–3408 (2019).

    PubMed  Google Scholar 

  172. Fauci, A. S., Marovich, M. A., Dieffenbach, C. W., Hunter, E. & Buchbinder, S. P. Immunology. Immune activation with HIV vaccines. Science 344, 49–51 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Penaloza-MacMaster, P. et al. Vaccine-elicited CD4 T cells induce immunopathology after chronic LCMV infection. Science 347, 278–282 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Landovitz, R. J. et al. Safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in low-risk HIV-uninfected individuals: HPTN 077, a phase 2a randomized controlled trial. PLoS Med. 15, e1002690 (2018).

    PubMed  PubMed Central  Google Scholar 

  175. Henderson, G. E. et al. Ethics of treatment interruption trials in HIV cure research: addressing the conundrum of risk/benefit assessment. J. Med. Ethics 44, 270–276 (2018).

    PubMed  Google Scholar 

  176. Clarridge, K. E. et al. Effect of analytical treatment interruption and reinitiation of antiretroviral therapy on HIV reservoirs and immunologic parameters in infected individuals. PLoS Pathog. 14, e1006792 (2018). HIV reservoir size and markers of immune activation and exhaustion were not elevated 6 to 12 months after analytical ART interruption, demonstrating the safety of treatment interruptions for evaluating therapeutic vaccines.

    PubMed  PubMed Central  Google Scholar 

  177. Strongin, Z. et al. Effect of short-term antiretroviral therapy interruption on levels of integrated HIV DNA. J. Virol. 92, e00285–18 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Salantes, D. B. et al. HIV-1 latent reservoir size and diversity are stable following brief treatment interruption. J. Clin. Invest. 128, 3102–3115 (2018).

    PubMed  PubMed Central  Google Scholar 

  179. Okoye, A. A. et al. Early antiretroviral therapy limits SIV reservoir establishment to delay or prevent post-treatment viral rebound. Nat. Med. 24, 1430–1440 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Kamphorst, A. O., Araki, K. & Ahmed, R. Beyond adjuvants: immunomodulation strategies to enhance T cell immunity. Vaccine 33, B21–B28 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Nishimura, Y. et al. Early antibody therapy can induce long-lasting immunity to SHIV. Nature 543, 559–563 (2017). Passive infusion of broadly neutralizing antibodies, but not ART, initiated early after SHIV infection, resulted in long-term control of viraemia in rhesus macaques due to a proposed vaccinal effect of antibody–antigen complexes that may facilitate induction of de novo antiviral CD8 + T cell responses.

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Rahman, M. A. & Robert-Guroff, M. Accelerating HIV vaccine development using non-human primate models. Expert. Rev. Vaccines 18, 61–73 (2019).

    PubMed  Google Scholar 

  183. Kalams, S. A. et al. Safety and comparative immunogenicity of an HIV-1 DNA vaccine in combination with plasmid interleukin 12 and impact of intramuscular electroporation for delivery. J. Infect. Dis. 208, 818–829 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Leal, L. et al. Phase I clinical trial of an intranodally administered mRNA-based therapeutic vaccine against HIV-1 infection. AIDS 32, 2533–2545 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Brekke, K. et al. Intranasal administration of a therapeutic HIV vaccine (Vacc-4×) induces dose-dependent systemic and mucosal immune responses in a randomized controlled trial. PLoS One 9, e112556 (2014).

    PubMed  PubMed Central  Google Scholar 

  186. Stephenson, K. E. et al. First-in-human randomized controlled trial of an oral, replicating adenovirus 26 vector vaccine for HIV-1. PLoS One 13, e0205139 (2018).

    PubMed  PubMed Central  Google Scholar 

  187. Tan, H. X. et al. Induction of vaginal-resident HIV-specific CD8 T cells with mucosal prime-boost immunization. Mucosal Immunol. 11, 994–1007 (2018).

    CAS  PubMed  Google Scholar 

  188. Shin, H. & Iwasaki, A. A vaccine strategy that protects against genital herpes by establishing local memory T cells. Nature 491, 463–467 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are grateful to the participants of all cited studies. We apologize to the many authors whose work was not cited in this review owing to space limitations. This work was supported by the US National Institutes of Health (NIH) grant UM1AI100663 and R37AI067073.

Author information

Authors and Affiliations

Authors

Contributions

All listed authors contributed to the writing, editing and preparation of this review article.

Corresponding author

Correspondence to Bruce D. Walker.

Ethics declarations

Competing interests

G.D.G. and B.D.W. have filed a provisional patent application (62/817,094) related to HIV vaccine design. D.R.C. declares no competing interests.

Additional information

Peer review information

Nature Reviews Immunology thanks P. Goulder, S. Lewin and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Collins, D.R., Gaiha, G.D. & Walker, B.D. CD8+ T cells in HIV control, cure and prevention. Nat Rev Immunol 20, 471–482 (2020). https://doi.org/10.1038/s41577-020-0274-9

Download citation

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41577-020-0274-9

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing