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
  • Published:

Why and where an HIV cure is needed and how it might be achieved

Abstract

Despite considerable global investment, only 60% of people who live with HIV currently receive antiretroviral therapy. The sustainability of current programmes remains unknown and key incidence rates are declining only modestly. Given the complexities and expenses associated with lifelong medication, developing an effective curative intervention is now a global priority. Here we review why and where a cure is needed, and how it might be achieved. We argue for expanding these efforts from resource-rich regions to sub-Saharan Africa and elsewhere: for any intervention to have an effect, region-specific biological, therapeutic and implementation issues must be addressed.

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: Pathways towards a cure.
Fig. 2: The cascade of treatment and control.
Fig. 3: HIV remission pathway.

Similar content being viewed by others

References

  1. Hütter, 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 

  2. Gupta, R. K. et al. HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-cell transplantation. Nature 568, 244–248 (2019).Two HIV-infected adults 1,2 with haematological malignancies were apparently cured of HIV after an effective stem-cell transplant from an allogeneic donor whose T cells lacked CCR5, a key co-receptor for virus entry.

    CAS  ADS  PubMed  Google Scholar 

  3. 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 

  4. 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).A subset of HIV-infected adults who start ART early and remain on therapy for a sustained period are able to effectively control HIV replication after treatment interruption; although the mechanism(s) at play remain unclear, these ‘post-treatment controllers’ provide strong evidence that the host–virus association can in some settings be slanted towards ART-free viral remission.

    PubMed  PubMed Central  Google Scholar 

  5. Deeks, S. G. et al. International AIDS Society global scientific strategy: towards an HIV cure 2016. Nat. Med. 22, 839–850 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Venter, W. D. F. et al. Dolutegravir plus two different prodrugs of tenofovir to treat HIV. N. Engl. J. Med. 381, 803–815 (2019).

    CAS  PubMed  Google Scholar 

  7. The NAMSAL ANRS 12313 Study Group. Dolutegravir-based or low-dose efavirenz-based regimen for the treatment of HIV-1. N. Engl. J. Med. 381, 816–826 (2019).

    Google Scholar 

  8. Rueda, S. et al. Examining the associations between HIV-related stigma and health outcomes in people living with HIV/AIDS: a series of meta-analyses. BMJ Open 6, e011453 (2016).

    PubMed  PubMed Central  Google Scholar 

  9. Katz, I. T. et al. Impact of HIV-related stigma on treatment adherence: systematic review and meta-synthesis. J. Int. AIDS Soc. 16, 18640 (2013).

    PubMed  PubMed Central  Google Scholar 

  10. Chu, C. E. et al. Exploring the social meaning of curing HIV: a qualitative study of people who inject drugs in Guangzhou, China. AIDS Res. Hum. Retroviruses 31, 78–84 (2015).

    PubMed  PubMed Central  Google Scholar 

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

    Google Scholar 

  12. Rodger, A. J. et al. Risk of HIV transmission through condomless sex in serodifferent gay couples with the HIV-positive partner taking suppressive antiretroviral therapy (PARTNER): final results of a multicentre, prospective, observational study. Lancet 393, 2428–2438 (2019).

    PubMed  PubMed Central  Google Scholar 

  13. UNAIDS. Global HIV & AIDS Statistics — 2019 Fact Sheet https://www.unaids.org/en/resources/fact-sheet (2019)

  14. Beacroft, L. & Hallett, T. B. The potential impact of a “curative intervention” for HIV: a modelling study. Glob. Health Res. Policy 4, 18 (2019).

    Google Scholar 

  15. Cuadros, D. F. et al. Towards UNAIDS Fast-Track goals: targeting priority geographic areas for HIV prevention and care in Zimbabwe. AIDS 33, 305–314 (2019).

    PubMed  Google Scholar 

  16. GBD 2017 HIV collaborators. Global, regional, and national incidence, prevalence, and mortality of HIV, 1980–2017, and forecasts to 2030, for 195 countries and territories: a systematic analysis for the Global Burden of Diseases, Injuries, and Risk Factors Study 2017. Lancet HIV 6, e831–e859 (2019).

  17. Moyo, S. et al. Cross-sectional estimates revealed high HIV incidence in Botswana rural communities in the era of successful ART scale-up in 2013–2015. PLoS ONE 13, e0204840 (2018).

    PubMed  PubMed Central  Google Scholar 

  18. UNAIDS. Fast-Track Update On Investments Needed In The AIDS Response https://www.unaids.org/sites/default/files/media_asset/UNAIDS_Reference_FastTrack_Update_on_investments_en.pdf (2016).

  19. Gelpi, A. & Tucker, J. D. A cure at last? Penicillin’s unintended consequences on syphilis control, 1944–1964. Sex. Transm. Infect. 91, 70 (2015).

    PubMed  PubMed Central  Google Scholar 

  20. Finzi, D. et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 278, 1295–1300 (1997).

    CAS  ADS  PubMed  Google Scholar 

  21. Wong, J. K. et al. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 278, 1291–1295 (1997).

    CAS  ADS  PubMed  Google Scholar 

  22. Chun, T. W. et al. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc. Natl Acad. Sci. USA 94, 13193–13197 (1997).

    CAS  ADS  PubMed  Google Scholar 

  23. Wiegand, A. et al. Single-cell analysis of HIV-1 transcriptional activity reveals expression of proviruses in expanded clones during ART. Proc. Natl Acad. Sci. USA 114, E3659–E3668 (2017).

    CAS  PubMed  Google Scholar 

  24. Cohn, L. B. et al. Clonal CD4+ T cells in the HIV-1 latent reservoir display a distinct gene profile upon reactivation. Nat. Med. 24, 604–609 (2018).Using single-cell analyses, the transcriptional profile of HIV-infected CD4 + T cells was characterized, revealing the expression of pathways that suppress HIV transcription.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Kuo, H.-H. et al. Anti-apoptotic protein BIRC5 maintains survival of HIV-1-infected CD4+ T cells. Immunity 48, 1183–1194 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Yukl, S. A. et al. HIV latency in isolated patient CD4+ T cells may be due to blocks in HIV transcriptional elongation, completion, and splicing. Sci. Transl. Med. 10, eaap9927 (2018).Multiple blocks to HIV transcription exist in infected CD4 + T cells; it may be necessary to overcome each using diverse approaches before sufficient amounts of HIV protein are made for the cell to be recognized and eliminated.

    PubMed  PubMed Central  Google Scholar 

  27. Ho, Y. C. et al. Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell 155, 540–551 (2013).Most (>90%) integrated HIV genomes are defective and unable to support HIV replication, complicating the measurement of the inducible replication-competent viral reservoir.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Hosmane, N. N. et al. Proliferation of latently infected CD4+ T cells carrying replication-competent HIV-1: potential role in latent reservoir dynamics. J. Exp. Med. 214, 959–972 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Descours, B. et al. CD32a is a marker of a CD4 T-cell HIV reservoir harbouring replication-competent proviruses. Nature 543, 564–567 (2017).

    CAS  ADS  PubMed  Google Scholar 

  30. Chomont, N. et al. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat. Med. 15, 893–900 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Fromentin, R. et al. CD4+ T cells expressing PD-1, TIGIT and LAG-3 contribute to HIV persistence during ART. PLoS Pathog. 12, e1005761 (2016).

    PubMed  PubMed Central  Google Scholar 

  32. 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).During effective antiretroviral therapy, transcriptionally active HIV is enriched in PD-1-expressing T follicular helper cells that reside in lymph nodes.

    CAS  PubMed  Google Scholar 

  33. McGary, C. S. et al. CTLA-4+PD-1 memory CD4+ T cells critically contribute to viral persistence in antiretroviral therapy-suppressed, SIV-infected rhesus macaques. Immunity 47, 776–788 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Chew, G. M. et al. TIGIT marks exhausted T cells, correlates with disease progression, and serves as a target for immune restoration in HIV and SIV infection. PLoS Pathog. 12, e1005349 (2016).

    PubMed  PubMed Central  Google Scholar 

  35. Hiener, B. et al. Identification of genetically intact HIV-1 proviruses in specific CD4+ T cells from effectively treated participants. Cell Rep. 21, 813–822 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Hogan, L. E. et al. Increased HIV-1 transcriptional activity and infectious burden in peripheral blood and gut-associated CD4+ T cells expressing CD30. PLoS Pathog. 14, e1006856 (2018).

    PubMed  PubMed Central  Google Scholar 

  37. Pardons, M. et al. Single-cell characterization and quantification of translation-competent viral reservoirs in treated and untreated HIV infection. PLoS Pathog. 15, e1007619 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Khoury, G. et al. Persistence of integrated HIV DNA in CXCR3 + CCR6 + memory CD4+ T cells in HIV-infected individuals on antiretroviral therapy. AIDS 30, 1511–1520 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Lee, G. Q. et al. Clonal expansion of genome-intact HIV-1 in functionally polarized Th1 CD4+ T cells. J. Clin. Invest. 127, 2689–2696 (2017).

    PubMed  PubMed Central  Google Scholar 

  40. Wacleche, V. S. et al. New insights into the heterogeneity of Th17 subsets contributing to HIV-1 persistence during antiretroviral therapy. Retrovirology 13, 59 (2016).

    PubMed  PubMed Central  Google Scholar 

  41. Wang, Z. et al. Expanded cellular clones carrying replication-competent HIV-1 persist, wax, and wane. Proc. Natl Acad. Sci. USA 115, E2575–E2584 (2018).

    CAS  PubMed  Google Scholar 

  42. Wagner, T. A. et al. Proliferation of cells with HIV integrated into cancer genes contributes to persistent infection. Science 345, 570–573 (2014).

    CAS  ADS  PubMed  PubMed Central  Google Scholar 

  43. Maldarelli, F. et al. Specific HIV integration sites are linked to clonal expansion and persistence of infected cells. Science 345, 179–183 (2014).As demonstrated in these two studies 42,43, proliferation of memory T cells is the main mechanism by which the reservoir is maintained indefinitely; during long-term therapy, the population of infected cells becomes increasingly clonal with integration of defective HIV genomes in genes associated with cell growth (including oncogenes) and/or within intergenic regions or silent genes.

    CAS  ADS  PubMed  PubMed Central  Google Scholar 

  44. Cohn, L. B. et al. HIV-1 integration landscape during latent and active infection. Cell 160, 420–432 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Einkauf, K. B. et al. Intact HIV-1 proviruses accumulate at distinct chromosomal positions during prolonged antiretroviral therapy. J. Clin. Invest. 129, 988–998 (2019).

    PubMed  PubMed Central  Google Scholar 

  46. Battivelli, E. et al. Distinct chromatin functional states correlate with HIV latency reactivation in infected primary CD4+ T cells. eLife 7, e34655 (2018).

    PubMed  PubMed Central  Google Scholar 

  47. Pinzone, M. R. et al. Longitudinal HIV sequencing reveals reservoir expression leading to decay which is obscured by clonal expansion. Nat. Commun. 10, 728 (2019).

    CAS  ADS  PubMed  PubMed Central  Google Scholar 

  48. Lee, G. Q. et al. HIV-1 DNA sequence diversity and evolution during acute subtype C infection. Nat. Commun. 10, 2737 (2019).

    ADS  PubMed  PubMed Central  Google Scholar 

  49. Huang, S. H. et al. Latent HIV reservoirs exhibit inherent resistance to elimination by CD8+ T cells. J. Clin. Invest. 128, 876–889 (2018).

    PubMed  PubMed Central  Google Scholar 

  50. Fletcher, C. V. et al. Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues. Proc. Natl Acad. Sci. USA 111, 2307–2312 (2014).

    CAS  ADS  PubMed  Google Scholar 

  51. Kearney, M. F. et al. Lack of detectable HIV-1 molecular evolution during suppressive antiretroviral therapy. PLoS Pathog. 10, e1004010 (2014).

    PubMed  PubMed Central  Google Scholar 

  52. Shan, L. et al. Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation. Immunity 36, 491–501 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 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 

  54. 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 

  55. Peretz, Y. et al. CD160 and PD-1 co-expression on HIV-specific CD8 T cells defines a subset with advanced dysfunction. PLoS Pathog. 8, e1002840 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Hersperger, A. R. et al. Increased HIV-specific CD8+ T-cell cytotoxic potential in HIV elite controllers is associated with T-bet expression. Blood 117, 3799–3808 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Tauriainen, J. et al. Perturbed CD8+ T cell TIGIT/CD226/PVR axis despite early initiation of antiretroviral treatment in HIV infected individuals. Sci. Rep. 7, 40354 (2017).

    CAS  ADS  PubMed  PubMed Central  Google Scholar 

  58. Takata, H. et al. Delayed differentiation of potent effector CD8+ T cells reducing viremia and reservoir seeding in acute HIV infection. Sci. Transl. Med. 9, eaag1809 (2017).

    PubMed  PubMed Central  Google Scholar 

  59. Ndhlovu, Z. M. et al. Augmentation of HIV-specific T cell function by immediate treatment of hyperacute HIV-1 infection. Sci. Transl. Med. 11, eaau0528 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Ndhlovu, Z. M. et al. Magnitude and kinetics of CD8+ T cell activation during hyperacute HIV infection impact viral set point. Immunity 43, 591–604 (2015).Studies 58–60 have shown that acute HIV infection is associated with a large CD8 + T cell response, which is initially effective but rapidly becomes less functional.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Yukl, S. A. et al. Challenges in detecting HIV persistence during potentially curative interventions: a study of the Berlin patient. PLoS Pathog. 9, e1003347 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Colby, D. J. et al. Rapid HIV RNA rebound after antiretroviral treatment interruption in persons durably suppressed in Fiebig I acute HIV infection. Nat. Med. 24, 923–926 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Henrich, T. J. et al. HIV-1 persistence following extremely early initiation of antiretroviral therapy (ART) during acute HIV-1 infection: an observational study. PLoS Med. 14, e1002417 (2017).Studies 62,63 have demonstrated that even with highly effective interventions that result in multi-log reductions in the reservoir, a small undetectable reservoir of replication-competent HIV can persist and rebound many months after ART is interrupted.

    PubMed  PubMed Central  Google Scholar 

  64. Henrich, T. J. et al. Antiretroviral-free HIV-1 remission and viral rebound after allogeneic stem cell transplantation: report of 2 cases. Ann. Intern. Med. 161, 319–327 (2014).

    PubMed  PubMed Central  Google Scholar 

  65. Persaud, D. et al. Absence of detectable HIV-1 viremia after treatment cessation in an infant. N. Engl. J. Med. 369, 1828–1835 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Fidler, S. et al. A pilot evaluation of whole blood finger-prick sampling for point-of-care HIV viral load measurement: the UNICORN study. Sci. Rep. 7, 13658 (2017).

    ADS  PubMed  PubMed Central  Google Scholar 

  67. Bruner, K. M. et al. A quantitative approach for measuring the reservoir of latent HIV-1 proviruses. Nature 566, 120–125 (2019).

    CAS  ADS  PubMed  PubMed Central  Google Scholar 

  68. Estes, J. D. et al. Defining total-body AIDS-virus burden with implications for curative strategies. Nat. Med. 23, 1271–1276 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Santangelo, P. J. et al. Whole-body immunoPET reveals active SIV dynamics in viremic and antiretroviral therapy-treated macaques. Nat. Methods 12, 427–432 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Keating, S. M. et al. HIV antibody level as a marker of HIV persistence and low-level viral replication. J. Infect. Dis. 216, 72–81 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Rothenberger, M. K. et al. Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption. Proc. Natl Acad. Sci. USA 112, E1126–E1134 (2015).

    CAS  PubMed  Google Scholar 

  72. Sneller, M. C. et al. A randomized controlled safety/efficacy trial of therapeutic vaccination in HIV-infected individuals who initiated antiretroviral therapy early in infection. Sci. Transl. Med. 9, eaan8848 (2017).

    PubMed  Google Scholar 

  73. Lelièvre, J.-D. & Hocqueloux, L. Unintended HIV-1 transmission to a sex partner in a study of a therapeutic vaccine candidate. J. Infect. Dis. 220, S5–S6 (2019).

    PubMed  Google Scholar 

  74. Julg, B. et al. Recommendations for analytical antiretroviral treatment interruptions in HIV research trials—report of a consensus meeting. Lancet HIV 6, e259–e268 (2019).

    PubMed  Google Scholar 

  75. Phillips, A. N. et al. Identifying key drivers of the impact of an HIV cure intervention in sub-Saharan Africa. J. Infect. Dis. 214, 73–79 (2016).

    PubMed  PubMed Central  Google Scholar 

  76. Paltiel, A. D. et al. Setting performance standards for a cost-effective human immunodeficiency virus cure strategy in South Africa. Open Forum Infect. Dis. 4, ofx081 (2017).

    PubMed  PubMed Central  Google Scholar 

  77. Dong, K. L. et al. Detection and treatment of Fiebig stage I HIV-1 infection in young at-risk women in South Africa: a prospective cohort study. Lancet HIV 5, e35–e44 (2018).

    PubMed  Google Scholar 

  78. 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 

  79. Violari, A. et al. A child with perinatal HIV infection and long-term sustained virological control following antiretroviral treatment cessation. Nat. Commun. 10, 412 (2019).

    CAS  ADS  PubMed  PubMed Central  Google Scholar 

  80. Frange, P. et al. HIV-1 virological remission lasting more than 12 years after interruption of early antiretroviral therapy in a perinatally infected teenager enrolled in the French ANRS EPF-CO10 paediatric cohort: a case report. Lancet HIV 3, e49–e54 (2016).

    PubMed  Google Scholar 

  81. Holt, N. et al. Human hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo. Nat. Biotechnol. 28, 839–847 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Peterson, C. W. et al. Differential impact of transplantation on peripheral and tissue-associated viral reservoirs: implications for HIV gene therapy. PLoS Pathog. 14, e1006956 (2018).

    PubMed  PubMed Central  Google Scholar 

  83. Haworth, K. G., Peterson, C. W. & Kiem, H. P. CCR5-edited gene therapies for HIV cure: closing the door to viral entry. Cytotherapy 19, 1325–1338 (2017).

    CAS  PubMed  Google Scholar 

  84. Yin, H., Kauffman, K. J. & Anderson, D. G. Delivery technologies for genome editing. Nat. Rev. Drug Discov. 16, 387–399 (2017).

    CAS  PubMed  Google Scholar 

  85. Davenport, M. P. et al. Functional cure of HIV: the scale of the challenge. Nat. Rev. Immunol. 19, 45–54 (2019).

    CAS  PubMed  Google Scholar 

  86. Kordelas, L. et al. Shift of HIV tropism in stem-cell transplantation with CCR5 Delta32 mutation. N. Engl. J. Med. 371, 880–882 (2014).

    PubMed  Google Scholar 

  87. Dash, P. K. et al. Sequential LASER ART and CRISPR treatments eliminate HIV-1 in a subset of infected humanized mice. Nat. Commun. 10, 2753 (2019).

    ADS  PubMed  PubMed Central  Google Scholar 

  88. Wang, G., Zhao, N., Berkhout, B. & Das, A. T. A combinatorial CRISPR–Cas9 attack on HIV-1 DNA extinguishes all infectious provirus in infected T cell cultures. Cell Rep. 17, 2819–2826 (2016).

    CAS  PubMed  Google Scholar 

  89. Martinez-Navio, J. M. et al. Adeno-associated virus delivery of anti-HIV monoclonal antibodies can drive long-term virologic suppression. Immunity 50, 567–575 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Priddy, F. H. et al. Adeno-associated virus vectored immunoprophylaxis to prevent HIV in healthy adults: a phase 1 randomised controlled trial. Lancet HIV 6, e230–e239 (2019).

    PubMed  PubMed Central  Google Scholar 

  91. Deeks, S. G. et al. A phase II randomized study of HIV-specific T-cell gene therapy in subjects with undetectable plasma viremia on combination antiretroviral therapy. Mol. Ther. 5, 788–797 (2002).

    CAS  PubMed  Google Scholar 

  92. June, C. H., O’Connor, R. S., Kawalekar, O. U., Ghassemi, S. & Milone, M. C. CAR T cell immunotherapy for human cancer. Science 359, 1361–1365 (2018).

    CAS  ADS  PubMed  Google Scholar 

  93. Zhen, A. et al. Long-term persistence and function of hematopoietic stem cell-derived chimeric antigen receptor T cells in a nonhuman primate model of HIV/AIDS. PLoS Pathog. 13, e1006753 (2017).

    PubMed  PubMed Central  Google Scholar 

  94. Leibman, R. S. et al. Supraphysiologic control over HIV-1 replication mediated by CD8 T cells expressing a re-engineered CD4-based chimeric antigen receptor. PLoS Pathog. 13, e1006613 (2017).

    PubMed  PubMed Central  Google Scholar 

  95. Anthony-Gonda, K. et al. Multispecific anti-HIV duoCAR-T cells display broad in vitro antiviral activity and potent in vivo elimination of HIV-infected cells in a humanized mouse model. Sci. Transl. Med. 11, eaav5685 (2019).

    PubMed  Google Scholar 

  96. Archin, N. M. et al. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature 487, 482–485 (2012).

    CAS  ADS  PubMed  PubMed Central  Google Scholar 

  97. Elliott, J. H. et al. Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy. PLoS Pathog. 10, e1004473 (2014).

    PubMed  PubMed Central  Google Scholar 

  98. Elliott, J. H. et al. Short-term administration of disulfiram for reversal of latent HIV infection: a phase 2 dose-escalation study. Lancet HIV 2, e520–e529 (2015).

    PubMed  PubMed Central  Google Scholar 

  99. Rasmussen, T. A. et al. Panobinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: a phase 1/2, single group, clinical trial. Lancet HIV 1, e13–e21 (2014).

    PubMed  Google Scholar 

  100. Søgaard, O. S. et al. The depsipeptide romidepsin reverses HIV-1 latency in vivo. PLoS Pathog. 11, e1005142 (2015).

    PubMed  PubMed Central  Google Scholar 

  101. Lim, S.-Y. et al. TLR7 agonists induce transient viremia and reduce the viral reservoir in SIV-infected rhesus macaques on antiretroviral therapy. Sci. Transl. Med. 10, eaao4521 (2018).

    PubMed  PubMed Central  Google Scholar 

  102. Vibholm, L. et al. Short-course Toll-like receptor 9 agonist treatment impacts innate immunity and plasma viremia in individuals with human immunodeficiency virus infection. Clin. Infect. Dis. 64, 1686–1695 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Laird, G. M. et al. Ex vivo analysis identifies effective HIV-1 latency-reversing drug combinations. J. Clin. Invest. 125, 1901–1912 (2015).

    PubMed  PubMed Central  Google Scholar 

  104. Macedo, A. B. et al. Dual TLR2 and TLR7 agonists as HIV latency-reversing agents. JCI Insight 3, e122673 (2018).

    Google Scholar 

  105. Rochat, M. A., Schlaepfer, E. & Speck, R. F. Promising role of Toll-like receptor 8 agonist in concert with prostratin for activation of silent HIV. J. Virol. 91, e02084-16 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Hill, A. L., Rosenbloom, D. I., Fu, F., Nowak, M. A. & Siliciano, R. F. Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1. Proc. Natl Acad. Sci. USA 111, 13475–13480 (2014).

    CAS  ADS  PubMed  Google Scholar 

  107. Mousseau, G. et al. The Tat inhibitor didehydro-cortistatin A prevents HIV-1 reactivation from latency. mBio 6, e00465-15 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Kessing, C. F. et al. In vivo suppression of HIV rebound by didehydro-cortistatin A, a “block-and-lock” strategy for HIV-1 treatment. Cell Rep. 21, 600–611 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Barr, E. L. & Jefferys, R. A landscape analysis of HIV cure-related clinical trials and observational studies in 2018. J. Virus Eradication http://viruseradication.com/journal-details/A_landscape_analysis_of_HIV_cure-related_clinical_trials_and_observational_studies_in_2018/ (2019).

  110. Conway, J. M. & Perelson, A. S. Post-treatment control of HIV infection. Proc. Natl Acad. Sci. USA 112, 5467–5472 (2015).

    CAS  ADS  PubMed  Google Scholar 

  111. Casazza, J. P. et al. Therapeutic vaccination expands and improves the function of the HIV-specific memory T-cell repertoire. J. Infect. Dis. 207, 1829–1840 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  ADS  PubMed  PubMed Central  Google Scholar 

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

    CAS  ADS  PubMed  PubMed Central  Google Scholar 

  114. Hessell, A. J. et al. Early short-term treatment with neutralizing human monoclonal antibodies halts SHIV infection in infant macaques. Nat. Med. 22, 362–368 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Borducchi, E. N. et al. Ad26/MVA therapeutic vaccination with TLR7 stimulation in SIV-infected rhesus monkeys. Nature 540, 284–287 (2016).

    CAS  ADS  PubMed  PubMed Central  Google Scholar 

  116. Borducchi, E. N. et al. Antibody and TLR7 agonist delay viral rebound in SHIV-infected monkeys. Nature 563, 360–364 (2018).In these two related non-human primate studies 115,116, a combination of immune therapies resulted in enhanced immune control and, in some cases, possible elimination of SIV/SHIV; these strategies are now being tested in people.

    CAS  ADS  PubMed  PubMed Central  Google Scholar 

  117. Nishimura, Y. et al. Early antibody therapy can induce long-lasting immunity to SHIV. Nature 543, 559–563 (2017).

    CAS  ADS  PubMed  PubMed Central  Google Scholar 

  118. Mendoza, P. et al. Combination therapy with anti-HIV-1 antibodies maintains viral suppression. Nature 561, 479–484 (2018).These two related studies 117,118 demonstrate that broadly neutralizing antibodies administered during a period of acute SHIV infection of non-human primates or immediately after interruption of ART in HIV-infected humans potentially induce long-term immune-mediated control (the ‘vaccinal effect’); in the case of SHIV-infected non-human primates, such suppression was shown to be mediated by CD8 + T cells.

    CAS  ADS  PubMed  PubMed Central  Google Scholar 

  119. Xu, L. et al. Trispecific broadly neutralizing HIV antibodies mediate potent SHIV protection in macaques. Science 358, 85–90 (2017).

    CAS  ADS  PubMed  PubMed Central  Google Scholar 

  120. Sung, J. A. et al. Dual-affinity re-targeting proteins direct T cell-mediated cytolysis of latently HIV-infected cells. J. Clin. Invest. 125, 4077–4090 (2015).

    PubMed  PubMed Central  Google Scholar 

  121. Leal, L. et al. New challenges in therapeutic vaccines against HIV infection. Expert Rev. Vaccines 16, 587–600 (2017).

    CAS  PubMed  Google Scholar 

  122. Gaiha, G. D. et al. Structural topology defines protective CD8+ T cell epitopes in the HIV proteome. Science 364, 480–484 (2019).

    CAS  Google Scholar 

  123. Fromentin, R. et al. PD-1 blockade potentiates HIV latency reversal ex vivo in CD4+ T cells from ART-suppressed individuals. Nat. Commun. 10, 814 (2019).

    CAS  ADS  PubMed  PubMed Central  Google Scholar 

  124. Gay, C. L. et al. Clinical trial of the anti-PD-L1 antibody BMS-936559 in HIV-1 infected participants on suppressive antiretroviral therapy. J. Infect. Dis. 215, 1725–1733 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Webb, G. M. et al. The human IL-15 superagonist ALT-803 directs SIV-specific CD8+ T cells into B-cell follicles. Blood Adv. 2, 76–84 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 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 

  127. Ananworanich, J. & Barré-Sinoussi, F. Is it time to abandon single intervention cure trials? Lancet HIV 2, e410–e411 (2015).

    PubMed  Google Scholar 

  128. Leth, S. et al. Combined effect of Vacc-4x, recombinant human granulocyte macrophage colony-stimulating factor vaccination, and romidepsin on the HIV-1 reservoir (REDUC): a single-arm, phase 1B/2A trial. Lancet HIV 3, e463–e472 (2016).

    PubMed  Google Scholar 

  129. Rossouw, T., Tucker, J. D., van Zyl G. U., Sikwesi, K. & Godfrey, C. Barriers to HIV remission research in low- and middle-income countries. J. Int. AIDS Soc. 20, 21521 (2017).

    ADS  PubMed  PubMed Central  Google Scholar 

  130. Kityo, C. et al. Lymphoid tissue fibrosis is associated with impaired vaccine responses. J. Clin. Invest. 128, 2763–2773 (2018).

    PubMed  PubMed Central  Google Scholar 

  131. Scully, E. P. et al. Sex-based differences in human immunodeficiency virus type 1 reservoir activity and residual immune activation. J. Infect. Dis. 219, 1084–1094 (2019).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

T.N. is supported in part by grants from the Bill & Melinda Gates Foundation, Gilead Sciences (grant no. 00406), the International AIDS Vaccine Initiative (IAVI) (UKZNRSA1001), the NIAID (R37AI067073) and the South African Department of Science and Technology through the National Research Foundation. T.N. is also partially supported through the sub-Saharan African Network for TB/HIV Research Excellence (SANTHE), a DELTAS Africa Initiative (grant no. DEL-15-006). The DELTAS Africa Initiative is an independent funding scheme of the African Academy of Sciences (AAS) Alliance for Accelerating Excellence in Science in Africa (AESA) and is supported by the New Partnership for Africa’s Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Wellcome Trust (grant no. 107752/Z/15/Z) and the UK government. J.M.M. is an employee of the Bill & Melinda Gates Foundation. S.G.D. is supported by the amfAR Institute for HIV Cure Research (amfAR 109301), the Delaney AIDS Research Enterprise (DARE; A127966), and the NIAID (K24 AI069994). We thank W. Greene for assistance with Fig. 1. The views expressed in this publication are those of the author(s) and not necessarily those of AAS, NEPAD Agency, Wellcome Trust, the UK government, the Bill & Melinda Gates Foundation or amfAR.

Author information

Authors and Affiliations

Authors

Contributions

T.N. and S.G.D. produced the first draft. J.M.M. provided substantial additions and edits. All three edited and approved the final version.

Corresponding author

Correspondence to Steven G. Deeks.

Ethics declarations

Competing interests

S.G.D. receives grant support from Gilead, Merck and ViiV. He is a member of the scientific advisory boards for BryoLogyx and Enochian Biosciences and has consulted for AbbVie, Biotron and Eli Lilly. T.N. receives grant support from Gilead.

Additional information

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

Ndung’u, T., McCune, J.M. & Deeks, S.G. Why and where an HIV cure is needed and how it might be achieved. Nature 576, 397–405 (2019). https://doi.org/10.1038/s41586-019-1841-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41586-019-1841-8

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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