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  • Opinion
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Towards an HIV cure: a global scientific strategy

Nature Reviews Immunology volume 12, pages 607–614 (2012)Cite this article

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Abstract

Given the limitations of antiretroviral therapy and recent advances in our understanding of HIV persistence during effective treatment, there is a growing recognition that a cure for HIV infection is both needed and feasible. The International AIDS Society convened a group of international experts to develop a scientific strategy for research towards an HIV cure. Several priorities for basic, translational and clinical research were identified. This Opinion article summarizes the group's recommended key goals for the international community.

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Figure 1: The impact of antiretroviral therapy on HIV reservoirs.
Figure 2: Mechanisms of HIV persistence during antiretroviral therapy.

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References

  1. Phillips, A. N., Neaton, J. & Lundgren, J. D. The role of HIV in serious diseases other than AIDS. AIDS 22, 2409–2418 (2008).

    Article  PubMed  Google Scholar 

  2. UN Secretary-General. Uniting for universal access: towards zero new HIV infections, zero discrimination and zero AIDS-related deaths (United Nations, 2011).

  3. Cohen M. S. et al. Prevention of HIV-1 infection with early antiretroviral therapy. N. Engl. J. Med. 365, 493–505 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Richman, D. D. et al. The challenge of finding a cure for HIV infection. Science 323, 1304–1307 (2009).

    Article  CAS  PubMed  Google Scholar 

  5. Trono, D. et al. HIV persistence and the prospect of long-term drug-free remissions for HIV-infected individuals. Science 329, 174–180 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Cohen, J. The emerging race to cure HIV infections. Science 332, 784–789 (2011).

    Article  CAS  PubMed  Google Scholar 

  7. Siliciano, J. D. et al. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nature Med. 9, 727–728 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Yukl, S. A. et al. Effect of raltegravir-containing intensification on HIV burden and T-cell activation in multiple gut sites of HIV-positive adults on suppressive antiretroviral therapy. AIDS 24, 2451–2460 (2010).

    Article  CAS  PubMed  Google Scholar 

  9. Buzon, M. J. et al. HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects. Nature Med. 16, 460–465 (2010).

    Article  PubMed  Google Scholar 

  10. Stebbing, J., Gazzard, B. & Douek, D. C. Where does HIV live? N. Engl. J. Med. 350, 1872–1880 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Wightman, F. et al. Both CD31+ and CD31− naive CD4+ T cells are persistent HIV type 1-infected reservoirs in individuals receiving antiretroviral therapy. J. Infect. Dis. 202, 1738–1748 (2010).

    Article  PubMed  Google Scholar 

  12. Kitchen, S. G. & Zack, J. A. CXCR4 expression during lymphopoiesis: implications for human immunodeficiency virus type 1 infection of the thymus. J. Virol. 71, 6928–6934 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Carter, C. C. et al. HIV-1 infects multipotent progenitor cells causing cell death and establishing latent cellular reservoirs. Nature Med. 16, 446–451 (2010).

    Article  CAS  PubMed  Google Scholar 

  14. Churchill, M. J. et al. Extensive astrocyte infection is prominent in human immunodeficiency virus-associated dementia. Ann. Neurol. 66, 253–258 (2009).

    Article  PubMed  Google Scholar 

  15. Burke, B. et al. Primary cell model for activation-inducible human immunodeficiency virus. J. Virol. 81, 7424–7434 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Saleh, S. et al. CCR7 ligands CCL19 and CCL21 increase permissiveness of resting memory CD4+ T cells to HIV-1 infection: a novel model of HIV-1 latency. Blood 110, 4161–4164 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Swiggard, W. J. et al. Human immunodeficiency virus type 1 can establish latent infection in resting CD4+ T cells in the absence of activating stimuli. J. Virol. 79, 14179–14188 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bosque, A. & Planelles, V. Induction of HIV-1 latency and reactivation in primary memory CD4+ T cells. Blood 113, 58–65 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Marini, A., Harper, J. M. & Romerio, F. An in vitro system to model the establishment and reactivation of HIV-1 latency. J. Immunol. 181, 7713–7720 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Jordan, A., Bisgrove, D. & Verdin, E. HIV reproducibly establishes a latent infection after acute infection of T cells in vitro. EMBO J. 22, 1868–1877 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Siliciano, R. F. & Greene, W. C. HIV latency. Cold Spring Harb. Perspect. Med. 1, a007096 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Sobhian, B. et al. HIV-1 Tat assembles a multifunctional transcription elongation complex and stably associates with the 7SK snRNP. Mol. Cell 38, 439–451 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Della Chiara, G. et al. Negative regulation of HIV-1 transcription by a heterodimeric NF-κB1/p50 and C-terminally truncated STAT5 complex. J. Mol. Biol. 410, 933–943 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. Tyagi, M., Pearson, R. J. & Karn, J. Establishment of HIV latency in primary CD4+ cells is due to epigenetic transcriptional silencing and P-TEFb restriction. J. Virol. 84, 6425–6437 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Williams, S. A. et al. NF-κB p50 promotes HIV latency through HDAC recruitment and repression of transcriptional initiation. EMBO J. 25, 139–149 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. Treand, C. et al. Requirement for SWI/SNF chromatin-remodeling complex in Tat-mediated activation of the HIV-1 promoter. EMBO J. 25, 1690–1699 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Blazkova, J. et al. CpG methylation controls reactivation of HIV from latency. PLoS Pathog. 5, e1000554 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Kauder, S. E., Bosque, A., Lindqvist, A., Planelles, V. & Verdin, E. Epigenetic regulation of HIV-1 latency by cytosine methylation. PLoS Pathog. 5, e1000495 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Van Lint, C., Emiliani, S., Ott, M. & Verdin, E. Transcriptional activation and chromatin remodeling of the HIV-1 promoter in response to histone acetylation. EMBO J. 15, 1112–1120 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Han, Y. et al. Orientation-dependent regulation of integrated HIV-1 expression by host gene transcriptional readthrough. Cell Host Microbe 4, 134–146 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  32. Bosque, A. Famiglietti, M., Weyrich, A. S., Goulston, C. & Planelles, V. Homeostatic proliferation fails to efficiently reactivate HIV-1 latently infected central memory CD4+ T cells. PLoS Pathog. 7, e1002288 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lehrman, G. et al. Depletion of latent HIV-1 infection in vivo: a proof-of-concept study. Lancet 366, 549–555 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Xing, S. et al. Disulfiram reactivates latent HIV-1 in a Bcl-2-transduced primary CD4+ T cell model without inducing global T cell activation. J. Virol. 85, 6060–6064 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Archin, N. M. et al. Expression of latent HIV induced by the potent HDAC inhibitor suberoylanilide hydroxamic acid. AIDS Res. Hum. Retroviruses 25, 207–212 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Contreras, X. et al. Suberoylanilide hydroxamic acid reactivates HIV from latently infected cells. J. Biol. Chem. 284, 6782–6789 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bouchat, S. et al. Histone methyltransferase inhibitors induce HIV-1 recovery in resting CD4+ T cells from HIV-1+ HAART-treated patients. AIDS 19 May 2012 (doi:10.1097/QAD.0b013e32835535f5).

    Article  CAS  PubMed  Google Scholar 

  38. Yukl, S. A. et al. Differences in HIV burden and immune activation within the gut of HIV-positive patients receiving suppressive antiretroviral therapy. J. Infect. Dis. 202, 1553–1561 (2010).

    Article  PubMed  Google Scholar 

  39. Deleage, C. et al. Human immunodeficiency virus infects human seminal vesicles in vitro and in vivo. Am. J. Pathol. 179, 2397–2408 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Horiike M. et al. Lymph nodes harbor viral reservoirs that cause rebound of plasma viremia in SIV-infected macaques upon cessation of combined antiretroviral therapy. Virology 423, 107–118 (2012).

    Article  CAS  PubMed  Google Scholar 

  41. Bourry, O. et al. Effect of a short-term HAART on SIV load in macaque tissues is dependent on time of initiation and antiviral diffusion. Retrovirology 7, 78 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  42. North, T. W. et al. Viral sanctuaries during highly active antiretroviral therapy in a nonhuman primate model for AIDS. J. Virol. 84, 2913–2922 (2010).

    Article  CAS  PubMed  Google Scholar 

  43. Pillai, S. K. et al. Semen-specific genetic characteristics of human immunodeficiency virus type 1 env. J. Virol. 79, 1734–1742 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kwara, A. et al. Antiretroviral drug concentrations and HIV RNA in the genital tract of HIV-infected women receiving long-term highly active antiretroviral therapy. Clin. Infect. Dis. 46, 719–725 (2008).

    Article  CAS  PubMed  Google Scholar 

  45. Geginat, J., Sallusto, F. & Lanzavecchia, A. Cytokine-driven proliferation and differentiation of human naive, central memory, and effector memory CD4+ T cells. J. Exp. Med. 194, 1711–1719 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Clements, J. E. et al. The central nervous system as a reservoir for simian immunodeficiency virus (SIV): steady-state levels of SIV DNA in brain from acute through asymptomatic infection. J. Infect. Dis. 186, 905–913 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Zeng, M. et al. Cumulative mechanisms of lymphoid tissue fibrosis and T cell depletion in HIV-1 and SIV infections. J. Clin. Invest. 121, 998–1008 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Brenchley, J. M. et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nature Med. 12, 1365–1371 (2006).

    Article  CAS  PubMed  Google Scholar 

  49. Hunt, P. W. et al. Valganciclovir reduces T cell activation in HIV-infected individuals with incomplete CD4+ T cell recovery on antiretroviral therapy. J. Infect. Dis. 203, 1474–1483 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Chun T. W. et al. HIV-infected individuals receiving effective antiviral therapy for extended periods of time continually replenish their viral reservoir. J. Clin. Invest. 115, 3250–3255 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Deeks, S. G. HIV infection, inflammation, immunosenescence, and aging. Annu. Rev. Med. 62, 141–155 (2011).

    Article  CAS  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hocqueloux, L. et al. Long-term immunovirologic control following antiretroviral therapy interruption in patients treated at the time of primary HIV-1 infection. AIDS 24, 1598–1601 (2010).

    Article  PubMed  Google Scholar 

  54. 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 

  55. Hilldorfer, B. B., Cillo, A. R., Besson, G. J., Bedison, M. A. & Mellors, J. W. New tools for quantifying HIV-1 reservoirs: plasma RNA single copy assays and beyond. Curr. HIV/AIDS Rep. 9, 91–100 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Lewin, S. R. & Rouzioux, C. HIV cure and eradication: how will we get from the laboratory to effective clinical trials? AIDS 25, 885–897 (2011).

    Article  PubMed  Google Scholar 

  57. Kieffer, T. L. et al. Genotypic analysis of HIV-1 drug resistance at the limit of detection: virus production without evolution in treated adults with undetectable HIV loads. J. Infect. Dis. 189, 1452–1465 (2004).

    Article  CAS  PubMed  Google Scholar 

  58. Dinoso, J. B. et al. Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. Proc. Natl Acad. Sci. USA 106, 9403–9408 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Gandhi, R. T. et al. The effect of raltegravir intensification on low-level residual viremia in HIV-infected patients on antiretroviral therapy: a randomized controlled trial. PLoS Med. 7, e1000321 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Hatano, H. et al. A randomized, controlled trial of raltegravir intensification in antiretroviral-treated, HIV-infected patients with a suboptimal CD4+ T cell response. J. Infect. Dis. 203, 960–968 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Sigal, A. et al. Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy. Nature 477, 95–98 (2011).

    Article  CAS  PubMed  Google Scholar 

  62. Buzon, M. J. et al. Deep molecular characterization of HIV-1 dynamics under suppressive HAART. PLoS Pathog. 7, e1002314 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Said, E. A. et al. Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection. Nature Med. 16, 452–459 (2010).

    Article  CAS  PubMed  Google Scholar 

  64. Sharova, N., Swingler, C., Sharkey, M. & Stevenson, M. Macrophages archive HIV-1 virions for dissemination in trans. EMBO J. 24, 2481–2489 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Topalian S. L et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Porter, D. L., Levine, B. L., Kalos, M., Bagg, A. & June, C. H. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365, 725–733 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Brooks, D. G. et al. Molecular characterization, reactivation, and depletion of latent HIV. Immunity 19, 413–423 (2003).

    Article  CAS  PubMed  Google Scholar 

  68. Berger, E. A., Moss, B. & Pastan, I. Reconsidering targeted toxins to eliminate HIV infection: you gotta have HAART. Proc. Natl Acad. Sci. USA 95, 11511–11513 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Garcia, F. et al. A therapeutic dendritic cell-based vaccine for HIV-1 infection. J. Infect. Dis. 203, 473–478 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Haynes, B. F. et al. Immune-correlates analysis of an HIV-1 vaccine efficacy trial. N. Engl. J. Med. 366, 1275–1286 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Levy, Y. et al. Enhanced T cell recovery in HIV-1-infected adults through IL-7 treatment. J. Clin. Invest. 119, 997–1007 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Yang, H. C. et al. Small-molecule screening using a human primary cell model of HIV latency identifies compounds that reverse latency without cellular activation. J. Clin. Invest. 119, 3473–3486 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Cameron, P. U. et al. Establishment of HIV-1 latency in resting CD4+ T cells depends on chemokine-induced changes in the actin cytoskeleton. Proc. Natl Acad. Sci. USA 107, 16934–16939 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Denton, P. W. et al. Generation of HIV latency in humanized BLT mice. J. Virol. 86, 630–634 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Hutter, G. et al. Long-term control of HIV by CCR5 delta32/delta32 stem-cell transplantation. N. Engl. J. Med. 360, 692–698 (2009).

    Article  PubMed  Google Scholar 

  76. Allers, K. et al. Evidence for the cure of HIV infection by CCR5Δ32/Δ32 stem cell transplantation. Blood 117, 2791–2799 (2011).

    Article  CAS  PubMed  Google Scholar 

  77. Ananworanich, J. et al. Impact of multi-targeted antiretroviral treatment on gut T cell depletion and HIV reservoir seeding during acute HIV infection. PLoS ONE 7, e33948 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Archin, N. M. et al. Immediate antiviral therapy appears to restrict resting CD4+ cell HIV-1 infection without accelerating the decay of latent infection. Proc. Natl Acad. Sci. USA 109, 9523–9528 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  80. DiGiusto, D. L. et al. RNA-based gene therapy for HIV with lentiviral vector-modified CD34+ cells in patients undergoing transplantation for AIDS-related lymphoma. Sci. Transl. Med. 2, 36ra43 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The International AIDS Society and the Scientific Working Group 'Towards an HIV Cure' acknowledge the fruitful input received from the members of the 'Towards an HIV Cure' Advisory Board, the members of the Working Group on Ethical Issues and the participants of the Stakeholders' Consultations. The full list of contributors can be found on the International AIDS Society website. The Global Scientific Strategy 'Towards an HIV Cure' is a project of the International AIDS Society in partnership with the French National Agency for Research on AIDS and Viral Hepatitis, the US National Institutes of Health, Sidaction and the Treatment Action Group. Stakeholders' Consultations have been organized in partnership with the Australasian Society for HIV Medicine, the European AIDS Treatment Group, the European AIDS Clinical Society and the US National Alliance of State and Territorial AIDS Directors. The authors would like to thank M. Eckert, B. Kadasia, R. Lamplough, S. Heidari, T. Torri and Y. Mameletzis from the International AIDS Society as well as O. Rescanière from the Institut Pasteur for their support in facilitating the development of the scientific strategy.

Author information

Authors and Affiliations

  1. Steven G. Deeks is at the University of California, San Francisco, USA.,

    Steven G. Deeks, Brigitte Autran, Ben Berkhout, Monsef Benkirane, Scott Cairns, Nicolas Chomont, Tae-Wook Chun, Melissa Churchill, Michele Di Mascio, Christine Katlama, Alain Lafeuillade, Alan Landay, Michael Lederman, Sharon R. Lewin, Frank Maldarelli, David Margolis, Martin Markowitz, Javier Martinez-Picado, James I. Mullins, John Mellors, Santiago Moreno, Una O'Doherty, Sarah Palmer, Marie-Capucine Penicaud, Matija Peterlin, Guido Poli, Jean-Pierre Routy, Christine Rouzioux, Guido Silvestri, Mario Stevenson, Amalio Telenti, Carine Van Lint, Eric Verdin, Ann Woolfrey, John Zaia & Françoise Barré-Sinoussi

Consortia

The International AIDS Society Scientific Working Group on HIV Cure

  • Steven G. Deeks
  • , Brigitte Autran
  • , Ben Berkhout
  • , Monsef Benkirane
  • , Scott Cairns
  • , Nicolas Chomont
  • , Tae-Wook Chun
  • , Melissa Churchill
  • , Michele Di Mascio
  • , Christine Katlama
  • , Alain Lafeuillade
  • , Alan Landay
  • , Michael Lederman
  • , Sharon R. Lewin
  • , Frank Maldarelli
  • , David Margolis
  • , Martin Markowitz
  • , Javier Martinez-Picado
  • , James I. Mullins
  • , John Mellors
  • , Santiago Moreno
  • , Una O'Doherty
  • , Sarah Palmer
  • , Marie-Capucine Penicaud
  • , Matija Peterlin
  • , Guido Poli
  • , Jean-Pierre Routy
  • , Christine Rouzioux
  • , Guido Silvestri
  • , Mario Stevenson
  • , Amalio Telenti
  • , Carine Van Lint
  • , Eric Verdin
  • , Ann Woolfrey
  • , John Zaia
  •  & Françoise Barré-Sinoussi

Corresponding author

Correspondence to Steven G. Deeks.

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Competing interests

The author declare no competing financial interests.

Additional information

A full list of authors appears in Box 1.

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The International AIDS Society Scientific Working Group on HIV Cure. Towards an HIV cure: a global scientific strategy. Nat Rev Immunol 12, 607–614 (2012). https://doi.org/10.1038/nri3262

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