International AIDS Society global scientific strategy: towards an HIV cure 2016

Nature Medicine - Tập 22 Số 8 - Trang 839-850 - 2016
Steven G. Deeks1, Sharon R. Lewin2,3, Anna Laura Ross4, Jintanat Ananworanich5,6, Monsef Benkirane7, Paula M. Cannon8, Nicolas Chomont9, Daniel C. Douek10, Jeffrey D. Lifson11, Ying‐Ru Lo12, Daniel R. Kuritzkes13, David M. Margolis14, John W. Mellors15, Deborah Persaud16, Joseph D. Tucker17, Françoise Barré‐Sinoussi18, Galit Alter19, Judith D. Auerbach1, Brigitte Autran20,21,22, Dan H. Barouch23,19, Marina Cavazzana24, Zhiwei Chen25, Giulio Maria Corbelli26, Joseph Larmarange27, Nir Eyal28, Sarah Fidler29, Laurindo Garcia30, Ross Cranston31, Gail E. Henderson14, Timothy J. Henrich13,1, Richard Jefferys32, HP Kiem33, Keymanthri Moodley34, Peter A. Newman35, Maik Nijhuis36, Melanie Ott37, Sarah Palmer38, Douglas D. Richman39, Asier Sáez‐Cirión18, Janet D. Siliciano40, Guido Silvestri41, Jerome Amir Singh42, Bruno Spire43, Martin Tolstrup44, Jan van Lunzen45, Rochelle P. Walensky46, Jerome A. Zack47
1Department of Medicine, University of California San Francisco, San Francisco, California, USA.
2Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Australia
3The Peter Doherty Institute for Infection and Immunity, University of Melbourne and Royal Melbourne Hospital, Melbourne, Australia
4International and Scientific Relations Office, ANRS, Paris, France.
5Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.
6US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
7Molecular Virology Lab, Institute of Human Genetics, CNRS UPR 1142, Université de Montpellier, Montpellier, France.
8Keck School of Medicine, University of Southern California, Los Angeles, California, USA
9CRCHUM and Department of Microbiology, Infectiology, and Immunology, Université de Montréal, Faculty of Medicine, Montréal, Quebec, Canada.
10Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
11AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland, USA.
12World Health Organization Regional Office for the Western Pacific, Manila, Philippines
13Brigham & Women’s Hospital, Boston, Massachusetts, USA
14University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA
15Division of Infectious Diseases, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
16Johns Hopkins University School of Medicine &Bloomberg School of Public Health, Baltimore, Maryland, USA.
17University of North Carolina-Project China, Guangzhou, China
18Institut Pasteur Paris, France;
19Ragon Institute of MGH, MIT, and Harvard, Boston, Massachusetts, USA
20AP-HP, Hôpital Pitié-Salpêtrière, Département d’immunologie, Paris, France
21INSERM, U1135, CIMI-Paris, Paris, France
22Sorbonne Universités, UPMC Univ Paris 06, CIMI-Paris, France.
23Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
24Centre d'Investigation Clinique en biothérapie, Hôpital Necker-Enfants Malades, Paris, France.
25Institut de Recherches Cliniques de Montréal, Université de Montréal, Montréal, Quebec, Canada
26European AIDS Treatment Group, Italy.
27Programme PAC-CI, Centre Hospitalier Universitaire de Treichville, Abidjan, Côte d'Ivoire.
28Harvard T. H. Chan School of Public Health, Department of Global Health and Population, Boston, Massachusetts, USA.
29Department of Medicine, Imperial College London, London, United Kingdom
30The B-Change Group, Manila, Philippines.
31National Institute of Mental Health, NIH, Bethesda, Maryland, USA.
32Treatment Action Group, New York, New York, USA.
33Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
34Centre for Medical Ethics and Law, Department of Medicine, Stellenbosch University, Western Cape, South Africa.
35Factor-Inwentash Faculty of Social Work, University of Toronto, Toronto, Ontario, Canada
36Joint Clinical Research Centre, Kampala, Uganda
37Gladstone Institutes, University of California, San Francisco, San Francisco, California, USA.
38Westmead Millennium Institute for Medical Research, University of Sydney, Sydney, Australia.
39Virginia San Diego Healthcare System and University of California, San Diego, San Diego, California, USA.
40Department of Medicine, Johns Hopkins University, School of Medicine, Baltimore, Maryland USA
41Yerkes National Primate Research Centre, Emory University, Atlanta, Georgia, USA.
42Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
43INSERM UMR_S912, Marseille, France.
44Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark
45ViiV Healthcare, London, United Kingdom.
46Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
47David Geffen School of Medicine at UCLA, Los Angeles, California, USA

Tóm tắt

Từ khóa


Tài liệu tham khảo

UN Joint Programme on HIV/AIDS (UNAIDS). The Gap Report, 2014; available at: http://www.refworld.org/docid/53f1e1604.html (accessed 23 April 2015).

Barré-Sinoussi, F., Ross, A.L. & Delfraissy, J.F. Past, present and future: 30 years of HIV research. Nat. Rev. Microbiol. 11, 877–883 (2013).

Deeks, S.G. et al. International AIDS Society Scientific Working Group on HIV Cure. Towards an HIV cure: a global scientific strategy. Nat. Rev. Immunol. 12, 607–614 (2012).

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).

Coull, J.J. et al. The human factors YY1 and LSF repress the human immunodeficiency virus type 1 long terminal repeat via recruitment of histone deacetylase 1. J. Virol. 74, 6790–6799 (2000).

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).

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

Ho, Y.C. et al. Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell 155, 540–551 (2013).

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

Hatano, H. et al. Increase in 2-long terminal repeat circles and decrease in D-dimer after raltegravir intensification in patients with treated HIV infection: a randomized, placebo-controlled trial. J. Infect. Dis. 208, 1436–1442 (2013).

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).

Lorenzo-Redondol, R. et al. Persistent HIV-1 replication maintains the HIV-1 reservoir during therapy. Nature (in the press).

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

Josefsson, L. et al. The HIV-1 reservoir in eight patients on long-term suppressive antiretroviral therapy is stable with few genetic changes over time. Proc. Natl. Acad. Sci. USA 110, E4987–E4996 (2013).

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

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

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).

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).

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).

Spina, C.A. et al. An in-depth comparison of latent HIV-1 reactivation in multiple cell model systems and resting CD4+ T cells from aviremic patients. PLoS Pathog. 9, e1003834 (2013).

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

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).

van Praag, R.M. et al. OKT3 and IL-2 treatment for purging of the latent HIV-1 reservoir in vivo results in selective long-lasting CD4+ T cell depletion. J. Clin. Immunol. 21, 218–226 (2001).

Bui, J.K., Mellors, J.W. & Cillo, A.R. HIV-1 virion production from single inducible proviruses following T-cell activation ex vivo. J. Virol. 90, 1673–1676 (2015).

Vandergeeten, C. et al. Interleukin-7 promotes HIV persistence during antiretroviral therapy. Blood 121, 4321–4329 (2013).

Jones, R.B. et al. Histone deacetylase inhibitors impair the elimination of HIV-infected cells by cytotoxic T-lymphocytes. PLoS Pathog. 10, e1004287 (2014).

Mousseau, G., Mediouni, S. & Valente, S.T. Targeting HIV transcription: the quest for a functional cure. Curr. Top. Microbiol. Immunol. 389, 121–145 (2015).

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

Barouch, D.H. & Deeks, S.G. Immunologic strategies for HIV-1 remission and eradication. Science 345, 169–174 (2014).

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

Yukl, S.A. et al. The distribution of HIV DNA and RNA in cell subsets differs in gut and blood of HIV-positive patients on ART: implications for viral persistence. J. Infect. Dis. 208, 1212–1220 (2013).

Chéret, A. et al. OPTIPRIM ANRS-147 Study Group. Combined ART started during acute HIV infection protects central memory CD4+ T cells and can induce remission. J. Antimicrob. Chemother. 70, 2108–2120 (2015).

Buzon, M.J. et al. HIV-1 persistence in CD4+ T cells with stem cell–like properties. Nat. Med. 20, 139–142 (2014).

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

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

Banga, R. et al. PD-1 and follicular helper T cells are responsible for persistent HIV-1 transcription in treated aviremic individuals. Nat. Med. http://dx.doi.org/10.1038/nm.4113 (2016).

Calantone, N. et al. Tissue myeloid cells in SIV-infected primates acquire viral DNA through phagocytosis of infected T cells. Immunity 41, 493–502 (2014).

Churchill, M.J., Cowley, D.J., Wesselingh, S.L., Gorry, P.R. & Gray, L.R. HIV-1 transcriptional regulation in the central nervous system and implications for HIV cure research. J. Neurovirol. 21, 290–300 (2015).

Honeycutt, J.B. et al. Macrophages sustain HIV replication in vivo independently of T cells. J. Clin. Invest. 126, 1353–1366 (2016).

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

Maldarelli, F. et al. HIV latency. Specific HIV integration sites are linked to clonal expansion and persistence of infected cells. Science 345, 179–183 (2014).

Imamichi, H. et al. Lifespan of effector memory CD4+ T cells determined by replication-incompetent integrated HIV-1 provirus. AIDS 28, 1091–1099 (2014).

Simonetti, F.R. et al. Clonally expanded CD4+ T cells can produce infectious HIV-1 in vivo. Proc. Natl. Acad. Sci. USA 113, 1883–1888 (2016).

Evans, V.A. et al. Myeloid dendritic cells induce HIV-1 latency in non-proliferating CD4+ T cells. PLoS Pathog. 9, e1003799 (2013).

Casazza, J.P. et al. VRC 101 Study Team. Therapeutic vaccination expands and improves the function of the HIV-specific memory T-cell repertoire. J. Infect. Dis. 207, 1829–1840 (2013).

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

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

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

Halper-Stromberg, A. et al. Broadly neutralizing antibodies and viral inducers decrease rebound from HIV-1 latent reservoirs in humanized mice. Cell 158, 989–999 (2014).

Barouch, D.H. et al. Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. Nature 503, 224–228 (2013).

Lynch, R.M. et al. VRC 601 Study Team. Virologic effects of broadly neutralizing antibody VRC01 administration during chronic HIV-1 infection. Sci. Transl. Med. 7, 319ra206 (2015).

Caskey, M. et al. Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature 522, 487–491 (2015).

Chun, T.W. et al. Broadly neutralizing antibodies suppress HIV in the persistent viral reservoir. Proc. Natl. Acad. Sci. USA 111, 13151–13156 (2014).

Euler, Z. & Alter, G. Exploring the potential of monoclonal antibody therapeutics for HIV-1 eradication. AIDS Res. Hum. Retroviruses 31, 13–24 (2015).

Pegu, A. et al. Activation and lysis of human CD4 cells latently infected with HIV-1. Nat. Commun. 6, 8447 (2015).

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).

Micci, L. et al. Interleukin-21 combined with ART reduces inflammation and viral reservoir in SIV-infected macaques. J. Clin. Invest. 125, 4497–4513 (2015).

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).

Stock, P.G. et al. Reduction of HIV persistence following transplantation in HIV-infected kidney transplant recipients. Am. J. Transplant. 14, 1136–1141 (2014).

Wightman, F. et al. Effect of ipilimumab on the HIV reservoir in an HIV-infected individual with metastatic melanoma. AIDS 29, 504–506 (2015).

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

Sáez-Cirión, A. et al. ANRS VISCONTI Study Group. 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).

Frange, P. et al. ANRS EPF-CO10 Pediatric Cohort and the ANRS EP47 VISCONTI study group. 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).

Whitney, J.B. et al. Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys. Nature 512, 74–77 (2014).

Denton, P.W. et al. Targeted cytotoxic therapy kills persisting HIV infected cells during ART. PLoS Pathog. 10, e1003872 (2014).

Del Prete, G.Q. et al. Elevated plasma viral loads in romidepsin-treated simian immunodeficiency virus–infected rhesus macaques on suppressive combination antiretroviral therapy. Antimicrob. Agents Chemother. 60, 1560–1572 (2015).

Marsden, M.D. et al. HIV latency in the humanized BLT mouse. J. Virol. 86, 339–347 (2012).

Persaud, D. et al. Pediatric HIV/AIDS Cohort Study. Influence of age at virologic control on peripheral blood human immunodeficiency virus reservoir size and serostatus in perinatally infected adolescents. JAMA Pediatr. 168, 1138–1146 (2014).

Ananworanich, J. et al. HIV-NAT 194 Study Group. Reduced markers of HIV persistence and restricted HIV-specific immune responses after early antiretroviral therapy in children. AIDS 28, 1015–1020 (2014).

Uprety, P. et al. Cell-associated HIV-1 DNA and RNA decay dynamics during early combination antiretroviral therapy in HIV-1-infected infants. Clin. Infect. Dis. 61, 1862–1870 (2015).

Muenchhoff, M., Prendergast, A.J. & Goulder, P.J. Immunity to HIV in early life. Front. Immunol. 5, 391 (2014).

Hütter, G. et al. Long-term control of HIV by CCR5 Δ32/Δ32 stem-cell transplantation. N. Engl. J. Med. 360, 692–698 (2009).

Cannon, P. & June, C. Chemokine receptor 5 knockout strategies. Curr. Opin. HIV AIDS 6, 74–79 (2011).

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).

Younan, P.M. et al. Positive selection of mC46-expressing CD4+ T cells and maintenance of virus specific immunity in a primate AIDS model. Blood 122, 179–187 (2013).

Hu, W. et al. RNA-directed gene editing specifically eradicates latent and prevents new HIV-1 infection. Proc. Natl. Acad. Sci. USA 111, 11461–11466 (2014).

Kitchen, S.G. et al. In vivo suppression of HIV by antigen specific T cells derived from engineered hematopoietic stem cells. PLoS Pathog. 8, e1002649 (2012).

Grupp, S.A. et al. Chimeric antigen receptor–modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368, 1509–1518 (2013).

Maude, S.L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014).

Balazs, A.B. et al. Vectored immunoprophylaxis protects humanized mice from mucosal HIV transmission. Nat. Med. 20, 296–300 (2014).

Gardner, M.R. et al. AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges. Nature 519, 87–91 (2015).

Smith, D.J. et al. Genetic engineering of hematopoietic stem cells to generate invariant natural killer T cells. Proc. Natl. Acad. Sci. USA 112, 1523–1528 (2015).

Tebas, P. et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N. Engl. J. Med. 370, 901–910 (2014).

Beard, B.C. et al. Efficient and stable MGMT-mediated selection of long-term repopulating stem cells in nonhuman primates. J. Clin. Invest. 120, 2345–2354 (2010).

Laird, G.M. et al. Rapid quantification of the latent reservoir for HIV-1 using a viral outgrowth assay. PLoS Pathog. 9, e1003398 (2013).

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

Crooks, A.M. et al. Precise quantitation of the latent HIV-1 reservoir: implications for eradication strategies. J. Infect. Dis. 212, 1361–1365 (2015).

Cillo, A.R. et al. Quantification of HIV-1 latency reversal in resting CD4+ T cells from patients on suppressive antiretroviral therapy. Proc. Natl. Acad. Sci. USA 111, 7078–7083 (2014).

Procopio, F.A. et al. A novel assay to measure the magnitude of the inducible viral reservoir in HIV-infected individuals. EBioMedicine 2, 872–881 (2015).

Metcalf Pate, K.A. et al. A murine viral outgrowth assay to detect residual HIV type 1 in patients with undetectable viral loads. J. Infect. Dis. 212, 1387–1396 (2015).

Eriksson, S. et al. Comparative analysis of measures of viral reservoirs in HIV-1 eradication studies. PLoS Pathog. 9, e1003174 (2013).

Burbelo, P.D. et al. HIV antibody characterization as a method to quantify reservoir size during curative interventions. J. Infect. Dis. 209, 1613–1617 (2014).

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

Li, J.Z. et al. The size of the expressed HIV reservoir predicts timing of viral rebound after treatment interruption. AIDS 30, 343–353 (2016).

Persaud, D. & Luzuriaga, K. Absence of HIV-1 after treatment cessation in an infant. N. Engl. J. Med. 370, 678 (2014).

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).

Hatano, H. et al. Cell-based measures of viral persistence are associated with immune activation and programmed cell death protein 1 (PD-1)-expressing CD4+ T cells. J. Infect. Dis. 208, 50–56 (2013).

Murray, J.M. et al. HIV DNA subspecies persist in both activated and resting memory CD4+ T cells during antiretroviral therapy. J. Virol. 88, 3516–3526 (2014).

Khoury, G. et al. Persistence of integrated HIV DNA in CXCR3+CCR6+memory CD4+ T-cells in HIV-infected individuals on antiretroviral therapy. AIDS (in the press).

van der Sluis, R.M. et al. Dendritic cell type-specific HIV-1 activation in effector T cells: implications for latent HIV-1 reservoir establishment. AIDS 29, 1003–1014 (2015).

Tucker, J.D., Rennie, S. & Social and Ethical Working Group on HIV Cure. Social and ethical implications of HIV cure research. AIDS 28, 1247–1250 (2014).

Henderson, G.E. The ethics of HIV “cure” research: what can we learn from consent forms? AIDS Res. Hum. Retroviruses 31, 56–63 (2015).

Peay, H.L. & Henderson, G.E. What motivates participation in HIV cure trials? A call for real-time assessment to improve informed consent. J. Virus Erad. 1, 51–53 (2015).

Moodley, K., Staunton, C., de Roubaix, M. & Cotton, M. HIV cure research in South Africa: a preliminary exploration of stakeholder perspectives. AIDS Care 28, 524–527 (2016).

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).

Lo, Y.R., Chu, C., Ananworanich, J., Excler, J.L. & Tucker, J.D. Stakeholder engagement in HIV cure research: Lessons learned from other HIV interventions and the way forward. AIDS Patient Care STDS 29, 389–399 (2015).

Newman, P.A. & Rubincam, C. Advancing community stakeholder engagement in biomedical HIV prevention trials: principles, practices and evidence. Expert Rev. Vaccines 13, 1553–1562 (2014).

Sax, P.E. et al. HIV cure strategies: how good must they be to improve on current antiretroviral therapy? PLoS One 9, e113031 (2014).

Freedberg, K.A. et al. The HIV cure research agenda: the role of mathematical modelling and cost-effectiveness analysis. J. Virus Erad. 1, 245–249 (2015).

Amon, J.J. Dangerous medicines: unproven AIDS cures and counterfeit antiretroviral drugs. Global. Health 4, 5 (2008).

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).

Fauci, A.S., Marston, H.D. & Folkers, G.K. An HIV cure: feasibility, discovery, and implementation. J. Am. Med. Assoc. 312, 335–336 (2014).

Tucker, J.D., Volberding, P.A., Margolis, D.M., Rennie, S. & Barré-Sinoussi, F. Words matter: Discussing research towards an HIV cure in research and clinical contexts. J. Acquir. Immune Defic. Syndr. 67, e110–e111 (2014).

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

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

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).

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).

Hurst, J. et al. Immunological biomarkers predict HIV-1 viral rebound after treatment interruption. Nat. Commun. 6, 8495 (2015).

Assoumou, L. et al. ANRS 116 SALTO study group. A low HIV-DNA level in peripheral blood mononuclear cells at antiretroviral treatment interruption predicts a higher probability of maintaining viral control. AIDS 29, 2003–2007 (2015).

Katlama, C. et al. EraMune-01 study team. Treatment intensification followed by interleukin-7 reactivates HIV without reducing total HIV DNA: a randomized trial. AIDS 30, 221–230 (2016).

Lorenzo-Redondo, R. et al. Persistent HIV-1 replication maintains the tissue reservoir during therapy. Nature 530, 51–56 (2016).

Wightman, F. et al. Entinostat is a histone deacetylase inhibitor selective for class 1 histone deacetylases and activates HIV production from latently infected primary T cells. AIDS 27, 2853–2862 (2013).

Jiang, G. et al. Reactivation of HIV latency by a newly modified Ingenol derivative via protein kinase Cδ-NF-κB signaling. AIDS 28, 1555–1566 (2014).

Boehm, D. et al. BET bromodomain-targeting compounds reactivate HIV from latency via a Tat-independent mechanism. Cell Cycle 12, 452–462 (2013).

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).

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