New challenges in therapeutic vaccines against HIV infection

References

• Palella FJ Jr., Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV outpatient study investigators. N Engl J Med. 1998;338(13):853–860.
   PubMed Web of Science ®Google Scholar
• Lima VD, Lourenço L, Yip B, et al. AIDS incidence and AIDS-related mortality in British Columbia, Canada, between 1981 and 2013: a retrospective study. The Lancet HIV. 2015;2(3):e92–e97.
   PubMed Web of Science ®Google Scholar
• Marrazzo JM, del Rio C, Holtgrave DR, et al. HIV prevention in clinical care settings: 2014 recommendations of the International Antiviral Society-USA panel. JAMA. 2014;312(4):390–409.
   PubMed Web of Science ®Google Scholar
• Group ISS. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med. 2015;373(9):795–807.
   Web of Science ®Google Scholar
• Gardner EM, McLees MP, Steiner JF, et al. The spectrum of engagement in HIV care and its relevance to test-and-treat strategies for prevention of HIV infection. Clin Infect Dis. 2011;52(6):793–800.
   PubMed Web of Science ®Google Scholar
• Campbell C, Ambrosioni J, Miro JM, et al. The continuum of HIV care in Catalonia. AIDS Care. 2015;27(12):1449–1454.
   PubMed Web of Science ®Google Scholar
• Fauci AS, Marston HD. Ending AIDS — is an HIV vaccine necessary? New England J Med. 2014;370(6):495–498.
   PubMed Web of Science ®Google Scholar
• Sidibe M. Newsmaker interview: michel Sidibe. New HIV infections drop, but treatment demands rise. Interview by Jon Cohen. Science. 2010;330(6009):1301.
   PubMed Web of Science ®Google Scholar
• Siliciano JD, Kajdas J, Finzi D, et al. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med. 2003;9(6):727–728.
   PubMed Web of Science ®Google Scholar
• Garcia F, Plana M, Vidal C, et al. Dynamics of viral load rebound and immunological changes after stopping effective antiretroviral therapy. AIDS. 1999;13(11):F79–F86.
   PubMed Web of Science ®Google Scholar
• El-Sadr WM, Lundgren J, Neaton JD, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355(22):2283–2296.
   PubMed Web of Science ®Google Scholar
• Plana M, Garcia F, Gallart T, et al. Immunological benefits of antiretroviral therapy in very early stages of asymptomatic chronic HIV-1 infection. AIDS. 2000;14(13):1921–1933.
   PubMed Web of Science ®Google Scholar
• Martinez E, Milinkovic A, Buira E, et al. Incidence and causes of death in HIV-infected persons receiving highly active antiretroviral therapy compared with estimates for the general population of similar age and from the same geographical area. HIV Med. 2007;8(4):251–258.
   PubMed Web of Science ®Google Scholar
• Deeks SG, Autran B, Berkhout B, et al. Towards an HIV cure: a global scientific strategy. Nat Rev Immunology. 2012;12(8):607–614.
   PubMed Web of Science ®Google Scholar
• Deeks SG, Lewin SR, Ross AL, et al. International AIDS Society global scientific strategy: towards an HIV cure 2016. Nat Med. 2016;22(8):839–850.
   PubMed Web of Science ®Google Scholar
• Garcia F, Leon A, Gatell JM, et al. Therapeutic vaccines against HIV infection. Hum Vaccin Immunother. 2012;8(5):569–581.
   PubMed Web of Science ®Google Scholar
• Autran B. Toward a cure for HIV-seeking effective therapeutic vaccine strategies. Eur J Immunol. 2015;45(12):3215–3221.
   PubMed Web of Science ®Google Scholar
• Pollard C, De Koker S, Saelens X, et al. Challenges and advances towards the rational design of mRNA vaccines. Trends Mol Med. 2013;19(12):705–713.
   PubMed Web of Science ®Google Scholar
• Pantaleo G, Levy Y. Therapeutic vaccines and immunological intervention in HIV infection: a paradigm change. Curr Opin HIV AIDS. 2016;11:576–584.
   PubMed Web of Science ®Google Scholar
• Barouch DH, Deeks SG. Immunologic strategies for HIV-1 remission and eradication. Science. 2014;345(6193):169–174.
   PubMed Web of Science ®Google Scholar
• Buzon MJ, Massanella M, Llibre JM, et al. HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects. Nat Med. 2010;16(4):460–465.
   PubMed Web of Science ®Google Scholar
• Henrich TJ, Hanhauser E, Marty FM, et al. Antiretroviral-free HIV-1 remission and viral rebound after allogeneic stem cell transplantationreport of 2 caseshiv-1 remission and viral rebound after allogeneic HSCT. Ann Intern Med. 2014;161(5):319–327.
   PubMed Web of Science ®Google Scholar
• Gardner MR, Kattenhorn LM, Kondur HR, et al. AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges. Nature. 2015.
   Web of Science ®Google Scholar
• Tebas P, Stein D, Tang WW, et al. Gene editing ofCCR5in autologous CD4 T cells of persons infected with HIV. New England J Med. 2014;370(10):901–910.
   PubMed Web of Science ®Google Scholar
• Lam S, Bollard C. T-cell therapies for HIV. Immunotherapy. 2013;5(4):407–414.
   PubMed Web of Science ®Google Scholar
• Garcia F, Climent N, Guardo AC, et al. A dendritic cell-based vaccine elicits t cell responses associated with control of HIV-1 replication. Sci Transl Med. 2013; 5(166)
   Web of Science ®Google Scholar
• Garcia F, Routy J-P. Challenges in dendritic cells-based therapeutic vaccination in HIV-1 infection Workshop in dendritic cell-based vaccine clinical trials in HIV-1. Vaccine. 2011;29(38):6454–6463.
   PubMed Web of Science ®Google Scholar
• Caskey M, Klein F, Lorenzi JC, et al. Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature. 2015;522(7557):487–491.
   PubMed Web of Science ®Google Scholar
• Lynch RM, Boritz E, Coates EE, et al. Virologic effects of broadly neutralizing antibody VRC01 administration during chronic HIV-1 infection. Sci Transl Med. 2015;7(319):319ra206–319ra206.
   PubMed Web of Science ®Google Scholar
• Scheid JF, Horwitz JA, Bar-On Y, et al. HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption. Nature. 2016;535(7613):556–560.
   PubMed Web of Science ®Google Scholar
• Karpas A, Hewlett IK, Hill F, et al. Polymerase chain reaction evidence for human immunodeficiency virus 1 neutralization by passive immunization in patients with AIDS and AIDS-related complex. Proc Natl Acad Sci USA. 1990;87(19):7613–7617.
   PubMed Web of Science ®Google Scholar
• Garcia F, Plana M, Ortiz G, et al. The virological and immunological consequences of structured treatment interruptions in chronic HIV-1 infection. AIDS. 2001;15(9):F29–F40.
   PubMed Web of Science ®Google Scholar
• Garcia F, Plana M, Arnedo M, et al. A cytostatic drug improves control of HIV-1 replication during structured treatment interruptions: a randomized study. AIDS. 2003;17(1):43–51.
   PubMed Web of Science ®Google Scholar
• Garcia F, Plana M, Arnedo M, et al. Effect of mycophenolate mofetil on immune response and plasma and lymphatic tissue viral load during and after interruption of highly active antiretroviral therapy for patients with chronic HIV infection - a randomized pilot study. Jaids-J Acquir Immune Defic Syndr. 2004;36(3):823–830.
   PubMed Web of Science ®Google Scholar
• Abrams D, Levy Y, Losso MH, et al. Interleukin-2 therapy in patients with HIV infection. N Engl J Med. 2009;361(16):1548–1559.
   PubMed Web of Science ®Google Scholar
• Katlama C, Lambert-Niclot S, Assoumou L, et al. Treatment intensification followed by interleukin-7 reactivates HIV without reducing total HIV DNA: a randomized trial. AIDS. 2016;30(2):221–230.
   PubMed Web of Science ®Google Scholar
• Micci L, Ryan ES, Fromentin R, et al. Interleukin-21 combined with ART reduces inflammation and viral reservoir in SIV-infected macaques. J Clin Invest. 2015;125(12):4497–4513.
   PubMed Web of Science ®Google Scholar
• Thiebaut R, Jarne A, Routy JP, et al. Repeated cycles of recombinant human interleukin 7 in HIV-infected patients with low CD4 T-cell reconstitution on antiretroviral therapy: results of 2 phase II multicenter studies. Clin Infect Dis. 2016;62(9):1178–1185.
   PubMed Web of Science ®Google Scholar
• Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439(7077):682–687.
   PubMed Web of Science ®Google Scholar
• Archin NM, Bateson R, Tripathy MK, et al. HIV-1 expression within resting CD4+ T cells after multiple doses of vorinostat. J Infect Dis. 2014;210(5):728–735.
   PubMed Web of Science ®Google Scholar
• Rasmussen TA, Tolstrup M, Brinkmann CR, 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. The Lancet HIV. 2014;1(1):e13–21.
   PubMed Web of Science ®Google Scholar
• Sogaard OS, Graversen ME, Leth S, et al. The depsipeptide romidepsin reverses HIV-1 latency in vivo. Plos Pathog. 2015;11(9):e1005142.
   PubMed Web of Science ®Google Scholar
• Richman DD, Margolis DM, Delaney M, et al. The challenge of finding a cure for HIV infection. Science. 2009;323(5919):1304–1307.
   PubMed Web of Science ®Google Scholar
• Conway JM, Perelson AS. Post-treatment control of HIV infection. Proc Natl Acad Sci USA. 2015;112(17):5467–5472.
   PubMed Web of Science ®Google Scholar
• Finzi D, Blankson J, Siliciano JD, et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med. 1999;5(5):512–517.
   PubMed Web of Science ®Google Scholar
• Plana M, Garcia F, Gallart T, et al. Lack of T-cell proliferative response to HIV-1 antigens after 1 year of highly active antiretroviral treatment in early HIV-1 disease. Lancet. 1998;352(9135):1194–1195.
   PubMed Web of Science ®Google Scholar
• Schmitz JE, Kuroda MJ, Santra S, et al. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science. 1999;283(5403):857–860.
   PubMed Web of Science ®Google Scholar
• Metzner KJ, Jin X, Lee FV, et al. Effects of in vivo CD8(+) T cell depletion on virus replication in rhesus macaques immunized with a live, attenuated simian immunodeficiency virus vaccine. J Exp Med. 2000;191(11):1921–1931.
   PubMed Web of Science ®Google Scholar
• De Quiros JC, Shupert WL, McNeil AC, et al. Resistance to replication of human immunodeficiency virus challenge in SCID-Hu mice engrafted with peripheral blood mononuclear cells of nonprogressors is mediated by CD8(+) T cells and associated with a proliferative response to p24 antigen. J Virol. 2000;74(4):2023–2028.
   PubMed Web of Science ®Google Scholar
• Cartwright EK, Spicer L, Smith SA, et al. CD8(+) lymphocytes are required for maintaining viral Suppression in SIV-infected macaques treated with short-term antiretroviral therapy. Immunity. 2016;45(3):656–668.
   PubMed Web of Science ®Google Scholar
• Letvin NL, Walker BD. Immunopathogenesis and immunotherapy in AIDS virus infections. Nat Med. 2003;9(7):861–866.
   PubMed Web of Science ®Google Scholar
• Johnson S, Eller M, Teigler JE, et al. Cooperativity of HIV-specific cytolytic CD4 T cells and CD8 T cells in control of HIV viremia. J Virol. 2015;89(15):7494–7505.
   PubMed Web of Science ®Google Scholar
• Becattini S, Latorre D, Mele F, et al. T cell immunity. Functional heterogeneity of human memory CD4(+) T cell clones primed by pathogens or vaccines. Science. 2015;347(6220):400–406.
   PubMed Web of Science ®Google Scholar
• Graziani GM, Angel JB. HIV-1. Immunogen: an overview of almost 30 years of clinical testing of a candidate therapeutic vaccine. Expert Opin Biol Ther. 2016;16(7):953–966.
   PubMed Web of Science ®Google Scholar
• Gorse GJ, Simionescu RE, Patel GB. Cellular immune responses in asymptomatic human immunodeficiency virus type 1 (HIV-1) infection and effects of vaccination with recombinant envelope glycoprotein of HIV-1. Clin Vaccine Immunol. 2006;13(1):26–32.
   PubMed Web of Science ®Google Scholar
• Dinges W, Girard PM, Podzamczer D, et al. The F4/AS01B HIV-1 vaccine candidate is safe and Immunogenic, but does not show viral efficacy in antiretroviral therapy-naive, HIV-1-infected adults: a randomized controlled trial. Medicine (Baltimore). 2016;95(6):e2673.
   PubMed Web of Science ®Google Scholar
• Dorrell L, Yang H, Iversen AK, et al. Therapeutic immunization of highly active antiretroviral therapy-treated HIV-1-infected patients: safety and immunogenicity of an HIV-1 gag/poly-epitope DNA vaccine. AIDS. 2005;19(12):1321–1323.
   PubMed Web of Science ®Google Scholar
• Papagno L, Alter G, Assoumou L, et al. Comprehensive analysis of virus-specific T-cells provides clues for the failure of therapeutic immunization with ALVAC-HIV vaccine. AIDS. 2011;25(1):27–36.
   PubMed Web of Science ®Google Scholar
• Angel JB, Routy JP, Tremblay C, et al. A randomized controlled trial of HIV therapeutic vaccination using ALVAC with or without Remune. AIDS. 2011;25(6):731–739.
   PubMed Web of Science ®Google Scholar
• Tung FY, Tung JK, Pallikkuth S, et al. A therapeutic HIV-1 vaccine enhances anti-HIV-1 immune responses in patients under highly active antiretroviral therapy. Vaccine. 2016;34(19):2225–2232.
   PubMed Web of Science ®Google Scholar
• Eron JJ Jr., Ashby MA, Giordano MF, et al. Randomised trial of MNrgp120 HIV-1 vaccine in symptomless HIV-1 infection. Lancet. 1996;348(9041):1547–1551.
   PubMed Web of Science ®Google Scholar
• Wright PF, Lambert JS, Gorse GJ, et al. Immunization with envelope MN rgp120 vaccine in human immunodeficiency virus-infected pregnant women. J Infect Dis. 1999;180(4):1080–1088.
   PubMed Web of Science ®Google Scholar
• Valentine FT, Kundu S, Haslett PA, et al. A randomized, placebo-controlled study of the immunogenicity of human immunodeficiency virus (HIV) rgp160 vaccine in HIV-infected subjects with > or = 400/mm3 CD4 T lymphocytes (AIDS Clinical Trials Group Protocol 137). J Infect Dis. 1996;173(6):1336–1346.
   PubMed Web of Science ®Google Scholar
• Wahren B, Bratt G, Persson C, et al. Improved cell-mediated immune responses in HIV-1-infected asymptomatic individuals after immunization with envelope glycoprotein gp160. J Acquir Immune Defic Syndr. 1994;7(3):220–229.
   PubMed Web of Science ®Google Scholar
• Ratto-Kim S, Sitz KV, Garner RP, et al. Repeated immunization with recombinant gp160 human immunodeficiency virus (HIV) envelope protein in early HIV-1 infection: evaluation of the T cell proliferative response. J Infect Dis. 1999;179(2):337–344.
   PubMed Web of Science ®Google Scholar
• Redfield RR, Birx DL, Ketter N, et al. A phase I evaluation of the safety and immunogenicity of vaccination with recombinant gp160 in patients with early human immunodeficiency virus infection. military medical consortium for applied retroviral research. N Engl J Med. 1991;324(24):1677–1684.
   PubMed Web of Science ®Google Scholar
• Schooley RT, Spino C, Kuritzkes D, et al. Two double-blinded, randomized, comparative trials of 4 human immunodeficiency virus type 1 (HIV-1) envelope vaccines in HIV-1-infected individuals across a spectrum of disease severity: AIDS Clinical Trials Groups 209 and 214. J Infect Dis. 2000;182(5):1357–1364.
   PubMed Web of Science ®Google Scholar
• Ensoli B, Nchabeleng M, Ensoli F, et al. HIV-Tat immunization induces cross-clade neutralizing antibodies and CD4(+) T cell increases in antiretroviral-treated South African volunteers: a randomized phase II clinical trial. Retrovirology. 2016;13(1):34.
   PubMed Web of Science ®Google Scholar
• Ensoli B, Bellino S, Tripiciano A, et al. Therapeutic immunization with HIV-1 Tat reduces immune activation and loss of regulatory T-cells and improves immune function in subjects on HAART. PLoS One. 2010;5(11):e13540.
   PubMed Web of Science ®Google Scholar
• Ensoli F, Cafaro A, Casabianca A, et al. HIV-1 Tat immunization restores immune homeostasis and attacks the HAART-resistant blood HIV DNA: results of a randomized phase II exploratory clinical trial. Retrovirology. 2015;12:1.
   PubMed Web of Science ®Google Scholar
• Loret EP, Darque A, Jouve E, et al. Intradermal injection of a Tat Oyi-based therapeutic HIV vaccine reduces of 1.5 log copies/mL the HIV RNA rebound median and no HIV DNA rebound following cART interruption in a phase I/II randomized controlled clinical trial. Retrovirology. 2016;13:21.
   PubMed Web of Science ®Google Scholar
• Goldstein G, Damiano E, Donikyan M, et al. HIV-1 Tat B-cell epitope vaccination was ineffectual in preventing viral rebound after ART cessation: HIV rebound with current ART appears to be due to infection with new endogenous founder virus and not to resurgence of pre-existing Tat-dependent viremia. Hum Vaccin Immunother. 2012;8(10):1425–1430.
   PubMed Web of Science ®Google Scholar
• Boffito M, Fox J, Bowman C, et al. Safety, immunogenicity and efficacy assessment of HIV immunotherapy in a multi-centre, double-blind, randomised, Placebo-controlled Phase Ib human trial. Vaccine. 2013;31(48):5680–5686.
   PubMed Web of Science ®Google Scholar
• Bartlett JA, Wasserman SS, Hicks CB, et al. Safety and immunogenicity of an HLA-based HIV envelope polyvalent synthetic peptide immunogen. DATRI 010 study group. Division of AIDS treatment research initiative. AIDS. 1998;12(11):1291–1300.
   PubMed Web of Science ®Google Scholar
• Vieillard V, Le Grand R, Dausset J, et al. A vaccine strategy against AIDS: an HIV gp41 peptide immunization prevents NKp44L expression and CD4+ T cell depletion in SHIV-infected macaques. Proc Natl Acad Sci USA. 2008;105(6):2100–2104.
   PubMed Web of Science ®Google Scholar
• Pollard RB, Rockstroh JK, Pantaleo G, et al. Safety and efficacy of the peptide-based therapeutic vaccine for HIV-1, Vacc-4x: a phase 2 randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2014;14(4):291–300.
   PubMed Web of Science ®Google Scholar
• Roman VR, Jensen KJ, Jensen SS, et al. Therapeutic vaccination using cationic liposome-adjuvanted HIV type 1 peptides representing HLA-supertype-restricted subdominant T cell epitopes: safety, immunogenicity, and feasibility in Guinea-Bissau. AIDS Res Hum Retroviruses. 2013;29(11):1504–1512.
   PubMed Web of Science ®Google Scholar
• Jacobson JM, Zheng L, Wilson CC, et al. The safety and immunogenicity of an interleukin-12-enhanced multiantigen DNA vaccine delivered by electroporation for the treatment of HIV-1 infection. J Acquir Immune Defic Syndr. 2016;71(2):163–171.
   PubMed Web of Science ®Google Scholar
• Vardas E, Stanescu I, Leinonen M, et al. Indicators of therapeutic effect in FIT-06, a phase II trial of a DNA vaccine, GTU((R))-multi-HIVB, in untreated HIV-1 infected subjects. Vaccine. 2012;30(27):4046–4054.
   PubMed Web of Science ®Google Scholar
• Rosenberg ES, Graham BS, Chan ES, et al. Safety and immunogenicity of therapeutic DNA vaccination in individuals treated with antiretroviral therapy during acute/early HIV-1 infection. PLoS One. 2010;5(5):e10555.
   PubMed Web of Science ®Google Scholar
• Casazza JP, Bowman KA, Adzaku S, et al. Therapeutic vaccination expands and improves the function of the HIV-specific memory T-cell repertoire. J Infect Dis. 2013;207(12):1829–1840.
   PubMed Web of Science ®Google Scholar
• Wilson CC, McKinney D, Anders M, et al. Development of a DNA vaccine designed to induce cytotoxic T lymphocyte responses to multiple conserved epitopes in HIV-1. J Immunology. 2003;171(10):5611–5623.
   PubMed Web of Science ®Google Scholar
• Rodriguez B, Asmuth DM, Matining RM, et al. Safety, tolerability, and immunogenicity of repeated doses of dermavir, a candidate therapeutic HIV vaccine, in HIV-infected patients receiving combination antiretroviral therapy: results of the ACTG 5176 trial. J Acquir Immune Defic Syndr. 2013;64(4):351–359.
   PubMed Web of Science ®Google Scholar
• Morrow MP, Tebas P, Yan J, et al. Synthetic consensus HIV-1 DNA induces potent cellular immune responses and synthesis of granzyme B, perforin in HIV infected individuals. Mol Therapy. 2015;23(3):591–601.
   PubMed Web of Science ®Google Scholar
• MacGregor RR, Boyer JD, Ugen KE, et al. Plasmid vaccination of stable HIV-positive subjects on antiviral treatment results in enhanced CD8 T-cell immunity and increased control of viral “blips”. Vaccine. 2005;23(17–18):2066–2073.
   PubMed Web of Science ®Google Scholar
• Thompson M, Heath SL, Sweeton B, et al. DNA/MVA vaccination of HIV-1 infected participants with viral suppression on antiretroviral therapy, followed by treatment interruption: elicitation of immune responses without control of re-emergent virus. PLoS One. 2016;11(10):e0163164.
   PubMed Web of Science ®Google Scholar
• Jacobson JM, Pat Bucy R, Spritzler J, et al. Evidence that intermittent structured treatment interruption, but not immunization with ALVAC-HIV vCP1452, promotes host control of HIV replication: the results of AIDS Clinical Trials Group 5068. J Infect Dis. 2006;194(5):623–632.
   PubMed Web of Science ®Google Scholar
• Autran B, Murphy RL, Costagliola D, et al. Greater viral rebound and reduced time to resume antiretroviral therapy after therapeutic immunization with the ALVAC-HIV vaccine (vCP1452). AIDS. 2008;22(11):1313–1322.
   PubMed Web of Science ®Google Scholar
• Smith KA, Andjelic S, Popmihajlov Z, et al. Immunotherapy with canarypox vaccine and interleukin-2 for HIV-1 infection: termination of a randomized trial. Plos Clin Trials. 2007;2(1):e5.
   PubMedGoogle Scholar
• Kilby JM, Bucy RP, Mildvan D, et al. A randomized, partially blinded phase 2 trial of antiretroviral therapy, HIV-specific immunizations, and interleukin-2 cycles to promote efficient control of viral replication (ACTG A5024). J Infect Dis. 2006;194(12):1672–1676.
   PubMed Web of Science ®Google Scholar
• Markowitz M, Jin X, Hurley A, et al. Discontinuation of antiretroviral therapy commenced early during the course of human immunodeficiency virus type 1 infection, with or without adjunctive vaccination. J Infect Dis. 2002;186(5):634–643.
   PubMed Web of Science ®Google Scholar
• Levy Y, Gahery-Segard H, Durier C, et al. Immunological and virological efficacy of a therapeutic immunization combined with interleukin-2 in chronically HIV-1 infected patients. AIDS. 2005;19(3):279–286.
   PubMed Web of Science ®Google Scholar
• Mothe B, Climent N, Plana M, et al. Safety and immunogenicity of a modified vaccinia Ankara-based HIV-1 vaccine (MVA-B) in HIV-1-infected patients alone or in combination with a drug to reactivate latent HIV-1. J Antimicrob Chemother. 2015;70(6):1833–1842.
   PubMed Web of Science ®Google Scholar
• Harrer E, Bauerle M, Ferstl B, et al. Therapeutic vaccination of HIV-1-infected patients on HAART with a recombinant HIV-1 nef-expressing MVA: safety, immunogenicity and influence on viral load during treatment interruption. Antivir Ther. 2005;10(2):285–300.
   PubMed Web of Science ®Google Scholar
• Emery S, Workman C, Puls RL, et al. Randomized, placebo-controlled, phase I/IIa evaluation of the safety and immunogenicity of fowlpox virus expressing HIV gag-pol and interferon-gamma in HIV-1 infected subjects. Hum Vaccin. 2005;1(6):232–238.
   PubMed Web of Science ®Google Scholar
• Mothe B, Manzardo C, Coll P et al. Safety and immunogenicity of ChAd.HIVconsv and MVA.HIVconsv therapeutic vaccines in a cohort of early treated HIV-­‐1 infected individuals. In: 8th IAS Conference on HIV Pathogenesis, Treatment & Prevention. (Ed.^(Eds). Vancouver, Canada, 2015.
   Google Scholar
• Kundu SK, Engleman E, Benike C, et al. A pilot clinical trial of HIV antigen-pulsed allogeneic and autologous dendritic cell therapy in HIV-infected patients. AIDS Res Hum Retroviruses. 1998;14(7):551–560.
   PubMed Web of Science ®Google Scholar
• Ide F, Nakamura T, Tomizawa M, et al. Peptide-loaded dendritic-cell vaccination followed by treatment interruption for chronic HIV-1 infection: a phase 1 trial. J Med Virol. 2006;78(6):711–718.
   PubMed Web of Science ®Google Scholar
• Connolly NC, Whiteside TL, Wilson C, et al. Therapeutic immunization with human immunodeficiency virus type 1 (HIV-1) peptide-loaded dendritic cells is safe and induces immunogenicity in HIV-1-infected individuals. Clin Vaccine Immunol. 2008;15(2):284–292.
   PubMed Web of Science ®Google Scholar
• Kloverpris H, Karlsson I, Bonde J, et al. Induction of novel CD8+ T-cell responses during chronic untreated HIV-1 infection by immunization with subdominant cytotoxic T-lymphocyte epitopes. AIDS. 2009;23(11):1329–1340.
   PubMed Web of Science ®Google Scholar
• Levy Y, Thiebaut R, Montes M, et al. Dendritic cell-based therapeutic vaccine elicits polyfunctional HIV-specific T-cell immunity associated with control of viral load. Eur J Immunol. 2014;44(9):2802–2810.
   PubMed Web of Science ®Google Scholar
• Lu W, Arraes LC, Ferreira WT, et al. Therapeutic dendritic-cell vaccine for chronic HIV-1 infection. Nat Med. 2004;10(12):1359–1365.
   PubMed Web of Science ®Google Scholar
• Gandhi RT, O’Neill D, Bosch RJ, et al. A randomized therapeutic vaccine trial of canarypox-HIV-pulsed dendritic cells vs. canarypox-HIV alone in HIV-1-infected patients on antiretroviral therapy. Vaccine. 2009;27(43):6088–6094.
   PubMed Web of Science ®Google Scholar
• Jacobson JM, Routy JP, Welles S, et al. Dendritic cell immunotherapy for HIV-1 infection using autologous HIV-1 RNA: a randomized, double-blind, placebo-controlled clinical trial. J Acquir Immune Defic Syndr. 2016;72(1):31–38.
   PubMed Web of Science ®Google Scholar
• Allard SD, De Keersmaecker B, De Goede AL. et al. A phase I/IIa immunotherapy trial of HIV-1-infected patients with Tat, Rev and Nef expressing dendritic cells followed by treatment interruption. Clin Immunol. 2012;142(3):252–268.
   PubMed Web of Science ®Google Scholar
• Van Gulck E, Vlieghe E, Vekemans M, et al. mRNA-based dendritic cell vaccination induces potent antiviral T-cell responses in HIV-1-infected patients. AIDS. 2012;26(4):F1–12.
   PubMed Web of Science ®Google Scholar
• Gandhi RT, Kwon DS, Macklin EA, et al. Immunization of HIV-1-infected persons with autologous Dendritic cells transfected with mRNA encoding HIV-1 gag and nef: results of a randomized, placebo-controlled clinical trial. J Acquir Immune Defic Syndr. 2016;71(3):246–253.
   PubMed Web of Science ®Google Scholar
• Macatangay BJ, Riddler SA, Wheeler ND, et al. Therapeutic vaccination with dendritic cells loaded with autologous HIV type 1-infected apoptotic cells. J Infect Dis. 2016;213(9):1400–1409.
   PubMed Web of Science ®Google Scholar
• Guardo AC, Joe PT, Miralles L, et al. Preclinical evaluation of an mRNA HIV vaccine combining rationally selected antigenic sequences and adjuvant signals (HTI-TriMix). AIDS. 2017;31(3):321–332.
   PubMed Web of Science ®Google Scholar
• Hansen SG, Ford JC, Lewis MS, et al. Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine. Nature. 2011;473(7348):523–527.
   PubMed Web of Science ®Google Scholar
• Hansen SG, Piatak M Jr., Ventura AB, et al. Immune clearance of highly pathogenic SIV infection. Nature. 2013;502(7469):100–104.
   PubMed Web of Science ®Google Scholar
• Hansen SG, Wu HL, Burwitz BJ, et al. Broadly targeted CD8+ T cell responses restricted by major histocompatibility complex E. Science. 2016;351(6274):714–720.
   PubMed Web of Science ®Google Scholar
• Petsch B, Schnee M, Vogel AB, et al. Protective efficacy of in vitro synthesized, specific mRNA vaccines against influenza A virus infection. Nat Biotechnol. 2012;30(12):1210–1216.
   PubMed Web of Science ®Google Scholar
• Weide B, Carralot JP, Reese A, et al. Results of the first phase I/II clinical vaccination trial with direct injection of mRNA. J Immunother (Hagerstown, Md.: 1997). 2008;31(2):180–188.
   PubMed Web of Science ®Google Scholar
• Weide B, Pascolo S, Scheel B, et al. Direct injection of protamine-protected mRNA: results of a phase 1/2 vaccination trial in metastatic melanoma patients. J Immunother (Hagerstown, Md.: 1997). 2009;32(5):498–507.
   PubMed Web of Science ®Google Scholar
• Rittig SM, Haentschel M, Weimer KJ, et al. Intradermal vaccinations with RNA coding for TAA generate CD8+ and CD4+ immune responses and induce clinical benefit in vaccinated patients. Mol Therapy. 2011;19(5):990–999.
   PubMed Web of Science ®Google Scholar
• Leth S, Schleimann MH, Nissen SK, 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. The Lancet HIV. 2016;3(10):e463–472.
   PubMed Web of Science ®Google Scholar
• Pen JJ, Keersmaecker BD, Heirman C, et al. Interference with PD-L1/PD-1 co-stimulation during antigen presentation enhances the multifunctionality of antigen-specific T cells. Gene Ther. 2014;21(3):262–271.
   PubMed Web of Science ®Google Scholar
• Ruiz A, Nomdedeu M, Ortega M, et al. Assessment of migration of HIV-1-loaded dendritic cells labeled with In-111-oxine used as a therapeutic vaccine in HIV-1-infected patients. Immunotherapy. 2009;1(3):347–354.
   PubMed Web of Science ®Google Scholar
• Van Lint S, Goyvaerts C, Maenhout S, et al. Preclinical evaluation of TriMix and antigen mRNA-based antitumor therapy. Cancer Res. 2012;72(7):1661–1671.
   PubMed Web of Science ®Google Scholar
• Flynn BJ, Kastenmuller K, Wille-Reece U, et al. Immunization with HIV Gag targeted to dendritic cells followed by recombinant New York vaccinia virus induces robust T-cell immunity in nonhuman primates. Proc Natl Acad Sci USA. 2011;108(17):7131–7136.
   PubMed Web of Science ®Google Scholar
• Emery S, Kelleher AD, Workman C, et al. Influence of IFNgamma co-expression on the safety and antiviral efficacy of recombinant fowlpox virus HIV therapeutic vaccines following interruption of antiretroviral therapy. Hum Vaccin. 2007;3(6):260–267.
   PubMed Web of Science ®Google Scholar
• Dewitte H, Van Lint S, Heirman C, et al. The potential of antigen and TriMix sonoporation using mRNA-loaded microbubbles for ultrasound-triggered cancer immunotherapy. J Controll Release. 2014;194:28–36.
   PubMed Web of Science ®Google Scholar
• Deng K, Pertea M, Rongvaux A, et al. Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations. Nature. 2015;517(7534):381–385.
   Web of Science ®Google Scholar
• Mothe B, Llano A, Ibarrondo J, et al. Definition of the viral targets of protective HIV-1-specific T cell responses. J Transl Med. 2011;9:208.
   PubMed Web of Science ®Google Scholar
• Im EJ, Hong JP, Roshorm Y, et al. Protective efficacy of serially up-ranked subdominant CD8+ T cell epitopes against virus challenges. Plos Pathog. 2011;7(5):e1002041.
   PubMed Web of Science ®Google Scholar
• Mothe B, Hu X, Llano A, et al. A human immune data-informed vaccine concept elicits strong and broad T-cell specificities associated with HIV-1 control in mice and macaques. J Transl Med. 2015;13:60.
   PubMed Web of Science ®Google Scholar
• Kreiter S, Vormehr M, Van De Roemer N, et al. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature. 2015;520(7549):692–696.
   PubMed Web of Science ®Google Scholar
• Carreno BM, Magrini V, Becker-Hapak M, et al. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Science. 2015.
   PubMed Web of Science ®Google Scholar
• Borthwick N, Ahmed T, Ondondo B, et al. Vaccine-elicited human T cells recognizing conserved protein regions inhibit HIV-1. Mol Therapy. 2014;22(2):464–475.
   PubMed Web of Science ®Google Scholar
• Letourneau S, Im EJ, Mashishi T, et al. Design and pre-clinical evaluation of a universal HIV-1 vaccine. PLoS One. 2007;2(10):e984.
   PubMed Web of Science ®Google Scholar
• Kulkarni V, Valentin A, Rosati M, et al. Altered response hierarchy and increased T-cell breadth upon HIV-1 conserved element DNA vaccination in macaques. PLoS One. 2014;9(1):e86254.
   PubMed Web of Science ®Google Scholar
• Kulkarni V, Rosati M, Valentin A, et al. HIV-1 p24(gag) derived conserved element DNA vaccine increases the breadth of immune response in mice. PLoS One. 2013;8(3):e60245.
   PubMed Web of Science ®Google Scholar
• Barouch DH, O’Brien KL, Simmons NL, et al. Mosaic HIV-1 vaccines expand the breadth and depth of cellular immune responses in rhesus monkeys. Nat Med. 2010;16(3):319–323.
   PubMed Web of Science ®Google Scholar
• Barouch Dan H, Stephenson Kathryn E, Borducchi Erica N, et al. Protective efficacy of a global HIV-1 mosaic vaccine against heterologous SHIV challenges in rhesus monkeys. Cell. 2013;155(3):531–539.
   PubMed Web of Science ®Google Scholar
• Hu X, Valentin A, Dayton F, et al. DNA prime-boost vaccine regimen to increase breadth, magnitude, and cytotoxicity of the cellular immune responses to subdominant gag epitopes of simian immunodeficiency virus and HIV. J Immunology. 2016;197:3999–4013.
   PubMed Web of Science ®Google Scholar
• Banga R, Procopio FA, Noto A, et al. PD-1(+) and follicular helper T cells are responsible for persistent HIV-1 transcription in treated aviremic individuals. Nat Med. 2016;22(7):754–761.
   PubMed Web of Science ®Google Scholar
• Fukazawa Y, Lum R, Okoye AA, et al. B cell follicle sanctuary permits persistent productive simian immunodeficiency virus infection in elite controllers. Nat Med. 2015;21(2):132–139.
   PubMed Web of Science ®Google Scholar
• He R, Hou S, Liu C, et al. Follicular CXCR5-expressing CD8+ T cells curtail chronic viral infection. Nature. 2016;537(7620):412–428.
   Web of Science ®Google Scholar
• Im SJ, Hashimoto M, Gerner MY, et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature. 2016;537:417–421.
   PubMed Web of Science ®Google Scholar
• Leong YA, Chen Y, Ong HS, et al. CXCR5+ follicular cytotoxic T cells control viral infection in B cell follicles. Nat Immunol. 2016.
   PubMed Web of Science ®Google Scholar
• Pavlakis GN, Valentin A, Bergamaschi C et al. Increased effector CD8 lymphocyte trafficking to lymph nodes induced by hetIL-15. In: 23rd Conference on Retroviruses and Opportunistic Infections February 22–25, 2016 Boston, MA, USA. (Ed.^(Eds). Boston. 2016.
   Google Scholar
• Hong E, Usiskin IM, Bergamaschi C, et al. Configuration-dependent presentation of multivalent IL-15: IL-15RalphaEnhances the antigen-specific T cell response and anti-tumor immunity. J Biol Chem. 2016;291(17):8931–8950.
   PubMed Web of Science ®Google Scholar
• Eron J, Gay CL, Bosch RJ et al. Safety, immunologic and virologic activity of anti-PD-L1 in HIV-1 participants on ART (abstract 25). In: 23rd Conference on Retroviruses and Opportunistic Infections February 22–25, 2016 Boston, MA, USA. (Ed.^(Eds) Boston, USA. 2016.
   Google Scholar
• Conlon KC, Lugli E, Welles HC, et al. Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer. J Clinical Oncology. 2015;33(1):74–82.
   PubMed Web of Science ®Google Scholar
• Rallon N, Mothe B, Lopez Bernaldo De Quiros JC, et al. Balance between activation and regulation of HIV-specific CD8+ T-cell response after modified vaccinia Ankara B therapeutic vaccination. AIDS. 2016;30(4):553–562.
   PubMed Web of Science ®Google Scholar
• Macatangay BJC, Szajnik ME, Whiteside TL, et al. Regulatory T cell suppression of gag-specific CD8+ T cell polyfunctional response after therapeutic vaccination of HIV-1-infected patients on ART. PLoS One. 2010;5(3):e9852.
   PubMed Web of Science ®Google Scholar
• Velu V, Titanji K, Zhu B, et al. Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature. 2009;458(7235):206–210.
   PubMed Web of Science ®Google Scholar
• Dyavar Shetty R, Velu V, Titanji K, et al. PD-1 blockade during chronic SIV infection reduces hyperimmune activation and microbial translocation in rhesus macaques. J Clin Invest. 2012;122(5):1712–1716.
   PubMed Web of Science ®Google Scholar
• Ribas A. Releasing the brakes on cancer immunotherapy. N Engl J Med. 2015;373:1490–1492.
   PubMed Web of Science ®Google Scholar
• Li JZ, Heisey A, Ahmed H, et al. Relationship of HIV reservoir characteristics with immune status and viral rebound kinetics in an HIV therapeutic vaccine study. AIDS. 2014;28:2649–2657.
   PubMed Web of Science ®Google Scholar
• Persaud D, Luzuriaga K, Ziemniak C, et al. Effect of therapeutic HIV recombinant poxvirus vaccines on the size of the resting CD4+ T-cell latent HIV reservoir. AIDS. 2011;25(18):2227–2234.
   PubMed Web of Science ®Google Scholar
• Andres C, Plana M, Guardo AC, et al. HIV-1 reservoir dynamics after vaccination and antiretroviral therapy interruption are associated with dendritic cell vaccine-induced T cell responses. J Virol. 2015;89(18):9189–9199.
   PubMed Web of Science ®Google Scholar
• Angel JB, Routy JP, Graziani GM, et al. The effect of therapeutic HIV vaccination with ALVAC-HIV with or without remune on the size of the viral reservoir (A CTN 173 substudy). J Acquir Immune Defic Syndr. 2015;70(2):122–128.
   PubMed Web of Science ®Google Scholar
• Deeks SG. HIV: shock and kill. Nature. 2012;487(7408):439–440.
   PubMed Web of Science ®Google Scholar
• Xing S, Bullen CK, Shroff NS, 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. 2011;85(12):6060–6064.
   PubMed Web of Science ®Google Scholar
• Graziani GM, Angel JB. Evaluating the efficacy of therapeutic HIV vaccines through analytical treatment interruptions. J Int AIDS Soc. 2015;18:20497.
   PubMed Web of Science ®Google Scholar
• Li JZ, Smith DM, Mellors JW. The need for treatment interruption studies and biomarker identification in the search for an HIV cure. AIDS. 2015;29(12):1429–1432.
   PubMed Web of Science ®Google Scholar
• Treasure GC, Aga E, Bosch RJ, et al. Brief report: relationship among viral load outcomes in HIV treatment interruption trials. J Acquir Immune Defic Syndr. 2016;72(3):310–313.
   PubMed Web of Science ®Google Scholar
• Martinez-Bonet M, Puertas MC, Fortuny C, et al. Establishment and replenishment of the viral reservoir in perinatally HIV-1-infected children initiating very early antiretroviral therapy. Clin Infect Dis. 2015;61:1169–1178.
   PubMed Web of Science ®Google Scholar
• Arnedo-Valero M, Garcia F, Gil C, et al. Risk of selecting de novo drug-resistance mutations during structured treatment interruptions in patients with chronic HIV infection. Clin Infect Dis. 2005;41(6):883–890.
   PubMed Web of Science ®Google Scholar
• Routy JP, Boulassel MR, Nicolette CA, et al. Assessing risk of a short-term antiretroviral therapy discontinuation as a read-out of viral control in immune-based therapy. J Med Virol. 2012;84(6):885–889.
   PubMed Web of Science ®Google Scholar
• Williams JP, Hurst J, Stohr W, et al. HIV-1 DNA predicts disease progression and post-treatment virological control. Elife. 2014;3:e03821.
   PubMed Web of Science ®Google Scholar