Progress Towards a Therapeutic HIV DNA Vaccine

References

• Chun T-W, Nickle DC, Justement JS, et al. Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy. J Infect Dis. 2008;197:714–720.
   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;9:727–728.
   PubMed Web of Science ®Google Scholar
• Braitstein P, Brinkhof MWG, Dabis F, et al. Mortality of HIV-1-infected patients in the first year of antiretroviral therapy: comparison between low-income and high-income countries. Lancet Lond Engl. 2006;367:817–824.
   PubMed Web of Science ®Google Scholar
• Crakes KR, Jiang G. Gut microbiome alterations during HIV/SIV infection: implications for HIV cure. Front Microbiol. 2019;10:1104.
   PubMed Web of Science ®Google Scholar
• Maldini CR, Claiborne DT, Okawa K, et al. Dual CD4-based CAR T cells with distinct costimulatory domains mitigate HIV pathogenesis in vivo. Nat Med. 2020;26:1776–1787.
   PubMed Web of Science ®Google Scholar
• Jülg B, Barouch DH. Novel immunological strategies for HIV-1 eradication. J Virus Erad. 2015;1:232–236.
   PubMedGoogle 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
• Baker B, Block B, Rothchild A, et al. Elite control of HIV infection: implications for vaccine design. Expert Opin Biol Ther. 2009;9:55–69.
   PubMed Web of Science ®Google Scholar
• Matano T, Shibata R, Siemon C, et al. Administration of an anti-CD8 monoclonal antibody interferes with the clearance of chimeric simian/human immunodeficiency virus during primary infections of rhesus macaques. J Virol. 1998;72:164–169.
   PubMed Web of Science ®Google Scholar
• Jin X, Bauer DE, Tuttleton SE, et al. Dramatic rise in plasma viremia after CD8+ T cell depletion in simian immunodeficiency Virus–infected macaques. J Exp Med. 1999;189:991–998.
   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;283:857–860.
   PubMed Web of Science ®Google Scholar
• Kunwar P, Hawkins N, Dinges WL, et al. Superior control of HIV-1 replication by CD8+ T cells targeting conserved epitopes: implications for HIV vaccine design. PloS One. 2013;8:e64405.
   PubMed Web of Science ®Google Scholar
• Kiepiela P, Ngumbela K, Thobakgale C, et al. CD8+ T-cell responses to different HIV proteins have discordant associations with viral load. Nat Med. 2007;13:46–53.
   PubMed Web of Science ®Google Scholar
• Borducchi EN, Cabral C, Stephenson KE, et al. Ad26/MVA therapeutic vaccination with TLR7 stimulation in SIV-infected rhesus monkeys. Nature. 2016;540:284–287.
   PubMed Web of Science ®Google Scholar
• Chouquet C, Autran B, Gomard E, et al. Correlation between breadth of memory HIV-specific cytotoxic T cells, viral load and disease progression in HIV infection. AIDS Lond Engl. 2002;16:2399–2407.
   PubMed Web of Science ®Google Scholar
• Fuller DH, Rajakumar P, Che JW, et al. Therapeutic DNA vaccine induces broad T cell responses in the gut and sustained protection from viral rebound and AIDS in SIV-infected rhesus macaques. PLoS ONE. 2012;7:e33715.
   PubMed Web of Science ®Google Scholar
• Betts MR, Nason MC, West SM, et al. HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood. 2006;107:4781–4789.
   PubMed Web of Science ®Google Scholar
• Hersperger AR, Pereyra F, Nason M, et al. Perforin expression directly ex vivo by HIV-specific CD8 T-cells is a correlate of HIV elite control. PLoS Pathog. 2010;6:e1000917.
   PubMed Web of Science ®Google Scholar
• Soghoian DZ, Streeck H. Cytolytic CD4(+) T cells in viral immunity. Expert Rev Vaccines. 2010;9:1453–1463.
   PubMed Web of Science ®Google Scholar
• Soghoian DZ, Jessen H, Flanders M, et al. HIV-specific cytolytic CD4 T cell responses during acute HIV infection predict disease outcome. Sci Transl Med. 2012;4:123ra25.
   PubMed Web of Science ®Google Scholar
• Douek DC, Brenchley JM, Betts MR, et al. HIV preferentially infects HIV-specific CD4+ T cells. Nature. 2002;417:95–98.
   PubMed Web of Science ®Google Scholar
• Wang Q, Zhang L. Broadly neutralizing antibodies and vaccine design against HIV-1 infection. Front Med. 2020;14:30–42.
   PubMed Web of Science ®Google Scholar
• Chahine EB, Durham SH. Ibalizumab: the first monoclonal antibody for the treatment of HIV-1 infection. Ann Pharmacother. 2021;55:230–239.
   PubMed Web of Science ®Google Scholar
• Shingai M, Nishimura Y, Klein F, et al. Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia. Nature. 2013;503:277–280.
   PubMed Web of Science ®Google Scholar
• Bruel T, Guivel-Benhassine F, Amraoui S, et al. Elimination of HIV-1-infected cells by broadly neutralizing antibodies. Nat Commun. 2016;7(1):10844.
   PubMedGoogle Scholar
• Ait-Ammar A, Kula A, Darcis G, et al. Current status of latency reversing agents facing the heterogeneity of HIV-1 cellular and tissue reservoirs. Front Microbiol. 2019;10:3060.
   PubMed Web of Science ®Google Scholar
• Singh V, Dashti A, Mavigner M, et al. Latency reversal 2.0: giving the immune system a seat at the table. Curr HIV/AIDS Rep. 2021;18:117–127.
   PubMed Web of Science ®Google Scholar
• Mu W, Carrillo MA, Kitchen SG. Engineering CAR T cells to target the HIV reservoir. Front Cell Infect Microbiol. 2020;10:410.
   PubMed Web of Science ®Google Scholar
• Qi J, Ding C, Jiang X, et al. Advances in developing CAR T-cell therapy for HIV cure. Front Immunol. 2020;11:361.
   PubMed Web of Science ®Google Scholar
• Peterson CW, Kiem H-P. Cell and gene therapy for HIV cure. Curr Top Microbiol Immunol. 2018;417:211–248.
   PubMed Web of Science ®Google Scholar
• Xiao Q, Guo D, Chen S. Application of CRISPR/Cas9-based gene editing in HIV-1/AIDS therapy. Front Cell Infect Microbiol. 2019;9:69.
   PubMed Web of Science ®Google Scholar
• Margolis DM, Archin NM, Cohen MS, et al. Curing HIV: seeking to target and clear persistent infection. Cell. 2020;181:189–206.
   PubMed Web of Science ®Google Scholar
• Collins DR, Gaiha GD, Walker BD. CD8+ T cells in HIV control, cure and prevention. Nat Rev Immunol. 2020;20:471–482.
   PubMed Web of Science ®Google Scholar
• Ward AR, Mota TM, Jones RB. Immunological approaches to HIV cure. Semin Immunol. 2021;51:101412.
   PubMed Web of Science ®Google Scholar
• Davenport MP, Khoury DS, Cromer D, et al. Functional cure of HIV: the scale of the challenge. Nat Rev Immunol. 2019;19:45–54.
   PubMed Web of Science ®Google Scholar
• Moodie Z, Metch B, Bekker L-G, et al. Continued follow-up of phambili phase 2b randomized HIV-1 vaccine trial participants supports increased HIV-1 acquisition among vaccinated men. PloS One. 2015;10:e0137666.
   PubMed Web of Science ®Google Scholar
• García 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;5:166ra2.
   PubMed Web of Science ®Google Scholar
• Liu MA. A comparison of plasmid DNA and mRNA as vaccine technologies. Vaccines (Basel). 2019;7:E37.
   PubMed Web of Science ®Google Scholar
• Sprent J, King C. COVID-19 vaccine side effects: the positives about feeling bad. Sci Immunol. 2021;6:eabj9256.
   PubMed Web of Science ®Google Scholar
• Boyer JD, Ugen KE, Chattergoon M, et al. DNA vaccination as anti-human immunodeficiency virus immunotherapy in infected chimpanzees. J Infect Dis. 1997;176:1501–1509.
   PubMed Web of Science ®Google Scholar
• MacGregor RR, Boyer JD, Ugen KE, et al. First human trial of a DNA-based vaccine for treatment of human immunodeficiency virus type 1 infection: safety and host response. J Infect Dis. 1998;178:92–100.
   PubMed Web of Science ®Google Scholar
• Calarota S, Bratt G, Nordlund S, et al. Cellular cytotoxic response induced by DNA vaccination in HIV-1-infected patients. Lancet. 1998;351:1320–1325.
   PubMed Web of Science ®Google Scholar
• Calarota SA, Leandersson A-C, Bratt G, et al. Immune responses in asymptomatic HIV-1-infected patients after HIV-DNA immunization followed by highly active antiretroviral treatment. J Immunol. 1999;163:2330–2338.
   PubMed Web of Science ®Google Scholar
• Zur Megede J, Sanders-Beer B, Silvera P, et al. A therapeutic SIV DNA vaccine elicits T-cell immune responses, but no sustained control of viremia in SIVmac239-infected rhesus macaques. AIDS Res Hum Retroviruses. 2008;24:1103–1116.
   PubMedGoogle Scholar
• Boyer JD, Chattergoon MA, Ugen KE, et al. Enhancement of cellular immune response in HIV-1 seropositive individuals: a DNA-based trial. Clin Immunol. 1999;90:100–107.
   PubMed Web of Science ®Google Scholar
• Boström A-C, Hejdeman B, Matsuda R, et al. Long-term persistence of vaccination and HAART to human immunodeficiency virus (HIV). Vaccine. 2004;22:1683–1691.
   PubMed Web of Science ®Google Scholar
• Wilson CC, Newman MJ, Livingston BD, et al. Clinical phase 1 testing of the safety and immunogenicity of an epitope-based DNA vaccine in human immunodeficiency virus type 1-infected subjects receiving highly active antiretroviral therapy. Clin Vaccine Immunol. 2008;15:986–994.
   PubMedGoogle Scholar
• Hokello J, Sharma AL, Tyagi M. An update on the HIV DNA vaccine strategy. Vaccines (Basel). 2021;9:605.
   PubMed Web of Science ®Google Scholar
• Larijani MS, Ramezani A, Sadat SM. Updated studies on the development of HIV therapeutic vaccine. Curr HIV Res. 2019;17:75–84.
   PubMed Web of Science ®Google Scholar
• Mekonnen ZA, Grubor-Bauk B, Masavuli MG, et al. Toward DNA-based T-cell mediated vaccines to target HIV-1 and hepatitis C virus: approaches to elicit localized immunity for protection. Front Cell Infect Microbiol. 2019;9:91.
   PubMed Web of Science ®Google Scholar
• Gamat-Huber M, Jeon D, Johnson LE, et al. Treatment combinations with DNA vaccines for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Cancers (Basel). 2020;12:E2831.
   PubMed Web of Science ®Google Scholar
• Rezaei T, Davoudian E, Khalili S, et al. Strategies in DNA vaccine for melanoma cancer. Pigment Cell Melanoma Res. 2021;34:869–891.
   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 Lond Engl. 2005;19:1321–1323.
   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;23:2066–2073.
   PubMed Web of Science ®Google Scholar
• Kobayashi M, Fitz L, Ryan M, et al. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med. 1989;170:827–845.
   PubMed Web of Science ®Google Scholar
• Gubler U, Chua AO, Schoenhaut DS, et al. Coexpression of two distinct genes is required to generate secreted bioactive cytotoxic lymphocyte maturation factor. Proc Natl Acad Sci U S A. 1991;88:4143–4147.
   PubMed Web of Science ®Google Scholar
• Becker TC, Wherry EJ, Boone D, et al. Interleukin 15 is required for proliferative renewal of virus-specific memory CD8 T cells. J Exp Med. 2002;195:1541–1548.
   PubMed Web of Science ®Google Scholar
• Rakhmilevich AL, Turner J, Ford MJ, et al. Gene gun-mediated skin transfection with interleukin 12 gene results in regression of established primary and metastatic murine tumors. Proc Natl Acad Sci U S A. 1996;93:6291–6296.
   PubMed Web of Science ®Google Scholar
• Xin KQ, Hamajima K, Sasaki S, et al. IL-15 expression plasmid enhances cell-mediated immunity induced by an HIV-1 DNA vaccine. Vaccine. 1999;17:858–866.
   PubMed Web of Science ®Google Scholar
• Halwani R, Boyer JD, Yassine-Diab B, et al. Therapeutic vaccination with simian immunodeficiency virus (SIV)-DNA + IL-12 or IL-15 induces distinct CD8 memory subsets in SIV-infected macaques. J Immunol Baltim Md 1950. 2008;180:7969–7979.
   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(®)-multi-HIVB, in untreated HIV-1 infected subjects. Vaccine. 2012;30:4046–4054.
   PubMed Web of Science ®Google Scholar
• Palma P, Romiti ML, Montesano C, et al. Therapeutic DNA vaccination of vertically HIV-infected children: report of the first pediatric randomised trial (PEDVAC). PloS One. 2013;8:e79957.
   PubMed Web of Science ®Google Scholar
• Raviprakash K, Ewing D, Simmons M, et al. Needle-free biojector injection of a dengue virus type 1 DNA vaccine with human immunostimulatory sequences and the GM-CSF gene increases immunogenicity and protection from virus challenge in Aotus monkeys. Virology. 2003;315:345–352.
   PubMed Web of Science ®Google Scholar
• Wang R, Epstein J, Baraceros FM, et al. Induction of CD4(+) T cell-dependent CD8(+) type 1 responses in humans by a malaria DNA vaccine. Proc Natl Acad Sci U S A. 2001;98:10817–10822.
   PubMed Web of Science ®Google Scholar
• Harris M, Joy R, Larsen G, et al. Enfuvirtide plasma levels and injection site reactions using a needle-free gas-powered injection system (Biojector). AIDS Lond Engl. 2006;20:719–723.
   PubMed Web of Science ®Google Scholar
• Loutfy MR, Harris M, Raboud JM, et al. A large prospective study assessing injection site reactions, quality of life and preference in patients using the Biojector vs standard needles for enfuvirtide administration. HIV Med. 2007;8:427–432.
   PubMed Web of Science ®Google Scholar
• Ake JA, Schuetz A, Pegu P, et al. Safety and immunogenicity of PENNVAX-G DNA prime administered by Biojector 2000 or CELLECTRA electroporation device with modified vaccinia Ankara-CMDR boost. J Infect Dis. 2017;216:1080–1090.
   PubMed Web of Science ®Google Scholar
• Choi AH-C, Smiley K, Basu M, et al. Protection of mice against rotavirus challenge following intradermal DNA immunization by Biojector needle-free injection. Vaccine. 2007;25:3215–3218.
   PubMed Web of Science ®Google Scholar
• Okuda K, Wada Y, Shimada M. Recent developments in preclinical DNA vaccination. Vaccines (Basel). 2014;2:89–106.
   PubMedGoogle Scholar
• Graham BS, Koup RA, Roederer M, et al. Phase 1 safety and immunogenicity evaluation of a multiclade HIV-1 DNA candidate vaccine. J Infect Dis. 2006;194:1650–1660.
   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:e10555.
   PubMed Web of Science ®Google Scholar
• Lisziewicz J, Trocio J, Whitman L, et al. DermaVir: a novel topical vaccine for HIV/AIDS. J Invest Dermatol. 2005;124:160–169.
   PubMed Web of Science ®Google Scholar
• Lisziewicz J, Trocio J, Xu J, et al. Control of viral rebound through therapeutic immunization with DermaVir. AIDS Lond Engl. 2005;19:35–43.
   PubMed Web of Science ®Google Scholar
• Lisziewicz J, Bakare N, Calarota SA, et al. Single DermaVir immunization: dose-dependent expansion of precursor/memory T cells against all HIV antigens in HIV-1 infected individuals. PLOS ONE. 2012;7:e35416.
   PubMed Web of Science ®Google Scholar
• Gudmundsdotter L, Wahren B, Haller BK, et al. Amplified antigen-specific immune responses in HIV-1 infected individuals in a double blind DNA immunization and therapy interruption trial. Vaccine. 2011;29:5558–5566.
   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 1999. 2013;64:351–359.
   PubMed Web of Science ®Google Scholar
• Widera G, Austin M, Rabussay D, et al. Increased DNA vaccine delivery and immunogenicity by electroporation in vivo. J Immunol Baltim Md 1950. 2000;164:4635–4640.
   Google Scholar
• Otten GR, Schaefer M, Doe B, et al. Potent immunogenicity of an HIV-1 gag-pol fusion DNA vaccine delivered by in vivo electroporation. Vaccine. 2006;24:4503–4509.
   PubMed Web of Science ®Google Scholar
• Zorn E, Nelson EA, Mohseni M, et al. IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood. 2006;108:1571–1579.
   PubMed Web of Science ®Google Scholar
• Valentin A, von Gegerfelt A, Rosati M, et al. Repeated DNA therapeutic vaccination of chronically SIV-infected macaques provides additional virological benefit. Vaccine. 2010;28:1962–1974.
   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 1999. 2016;71:163–171.
   PubMed Web of Science ®Google Scholar
• Tunggal HC, Munson PV, O’Connor MA, et al. Effects of therapeutic vaccination on the control of SIV in rhesus macaques with variable responsiveness to antiretroviral drugs. PloS One. 2021;16:e0253265.
   PubMed Web of Science ®Google Scholar
• Holechek SA, McAfee MS, Nieves LM, et al. Retinaldehyde dehydrogenase 2 as a molecular adjuvant for enhancement of mucosal immunity during DNA vaccination. Vaccine. 2016;34:5629–5635.
   PubMed Web of Science ®Google Scholar
• Roos A-K, Moreno S, Leder C, et al. Enhancement of cellular immune response to a prostate cancer DNA vaccine by intradermal electroporation. Mol Ther J Am Soc Gene Ther. 2006;13:320–327.
   PubMed Web of Science ®Google Scholar
• Eisenbraun MD, Fuller DH, Haynes JR. Examination of parameters affecting the elicitation of humoral immune responses by particle bombardment-mediated genetic immunization. DNA Cell Biol. 1993;12:791–797.
   PubMed Web of Science ®Google Scholar
• Tang DC, DeVit M, Johnston SA. Genetic immunization is a simple method for eliciting an immune response. Nature. 1992;356:152–154.
   PubMed Web of Science ®Google Scholar
• Tőke ER, Lőrincz O, Csiszovszki Z, et al. Exploitation of Langerhans cells for in vivo DNA vaccine delivery into the lymph nodes. Gene Ther. 2014;21:566–574.
   PubMed Web of Science ®Google Scholar
• Deckers J, Hammad H, Hoste E. Langerhans cells: sensing the environment in health and disease. Front Immunol. 2018;9:93.
   PubMed Web of Science ®Google Scholar
• Stoecklinger A, Grieshuber I, Scheiblhofer S, et al. Epidermal Langerhans cells are dispensable for humoral and cell-mediated immunity elicited by gene gun immunization. J Immunol Baltim Md 1950. 2007;179:886–893.
   Google Scholar
• Loudon PT, Yager EJ, Lynch DT, et al. GM-CSF increases mucosal and systemic immunogenicity of an H1N1 influenza DNA vaccine administered into the epidermis of non-human primates. PloS One. 2010;5:e11021.
   PubMed Web of Science ®Google Scholar
• Koday MT, Leonard JA, Munson P, et al. Multigenic DNA vaccine induces protective cross-reactive T cell responses against heterologous influenza virus in nonhuman primates. PloS One. 2017;12:e0189780.
   PubMed Web of Science ®Google Scholar
• Roy MJ, Wu MS, Barr LJ, et al. Induction of antigen-specific CD8+ T cells, T helper cells, and protective levels of antibody in humans by particle-mediated administration of a hepatitis B virus DNA vaccine. Vaccine. 2000;19:764–778.
   PubMed Web of Science ®Google Scholar
• Fuller DH, Rajakumar PA, Wu MS, et al. DNA immunization in combination with effective antiretroviral drug therapy controls viral rebound and prevents simian AIDS after treatment is discontinued. Virology. 2006;348:200–215.
   PubMed Web of Science ®Google Scholar
• Rolland M, Nickle DC, Mullins JI. HIV-1 group M conserved elements vaccine. PLoS Pathog. 2007;3:e157.
   PubMed Web of Science ®Google Scholar
• Munson P, Liu Y, Bratt D, et al. Therapeutic conserved elements (CE) DNA vaccine induces strong T-cell responses against highly conserved viral sequences during simian-human immunodeficiency virus infection. Hum Vaccines Immunother. 2018;14:1820–1831.
   PubMed Web of Science ®Google Scholar
• Jones T. Vacc-4x, a therapeutic vaccine comprised of four engineered peptides for the potential treatment of HIV infection. Curr Opin Invest Drugs Lond Engl 2000. 2010;11:964–970.
   PubMedGoogle Scholar
• Brekke K, Lind A, Holm-Hansen C, et al. Intranasal administration of a therapeutic HIV vaccine (Vacc-4x) induces dose-dependent systemic and mucosal immune responses in a randomized controlled trial. PloS One. 2014;9:e112556.
   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. Lancet HIV. 2016;3:e463–472.
   PubMed Web of Science ®Google Scholar
• Hancock G, Morón-López S, Kopycinski J, et al. Evaluation of the immunogenicity and impact on the latent HIV-1 reservoir of a conserved region vaccine, MVA.HIVconsv, in antiretroviral therapy-treated subjects. J Int AIDS Soc. 2017;20:21171.
   PubMed Web of Science ®Google Scholar
• Hanke T. Aiming for protective T-cell responses: a focus on the first generation conserved-region HIVconsv vaccines in preventive and therapeutic clinical trials. Expert Rev Vaccines. 2019;18:1029–1041.
   PubMed Web of Science ®Google Scholar
• Mothe B, Rosás-Umbert M, Coll P, et al. HIVconsv vaccines and romidepsin in early-treated HIV-1-infected individuals: safety, immunogenicity and effect on the viral reservoir (study BCN02). Front Immunol. 2020;11:823.
   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
• Garcia-Bates TM, Palma ML, Anderko RR, et al. Dendritic cells focus CTL responses toward highly conserved and topologically important HIV-1 epitopes. EBioMedicine. 2021;63:103175.
   PubMed Web of Science ®Google Scholar
• Korber B, Fischer W. T cell-based strategies for HIV-1 vaccines. Hum Vaccines Immunother. 2020;16:713–722.
   PubMed Web of Science ®Google Scholar
• Mylvaganam G, Yanez AG, Maus M, et al. Toward T cell-mediated control or elimination of HIV reservoirs: lessons from cancer immunology. Front Immunol. 2019;10:2109.
   PubMed Web of Science ®Google Scholar
• Shacklett BL, Ferre AL, Kiniry BE. Defining T cell tissue residency in humans: implications for HIV pathogenesis and vaccine design. Curr HIV/AIDS Rep. 2020;17:109–117.
   PubMed Web of Science ®Google Scholar
• Chun TW, Finzi D, Margolick J, et al. In vivo fate of HIV-1-infected T cells: quantitative analysis of the transition to stable latency. Nat Med. 1995;1:1284–1290.
   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;5:512–517.
   PubMed Web of Science ®Google Scholar
• Rasmussen TA, Tolstrup M, Søgaard OS. Reversal of latency as part of a cure for HIV-1. Trends Microbiol. 2016;24:90–97.
   PubMed Web of Science ®Google Scholar
• Archin NM, Liberty AL, Kashuba AD, et al. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature. 2012;487:482–485.
   PubMed Web of Science ®Google Scholar
• Elliott JH, Wightman F, Solomon A, et al. Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy. PLoS Pathog. 2014;10:e1004473.
   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;210:728–735.
   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. Lancet HIV. 2014;1:e13–21.
   PubMed Web of Science ®Google Scholar
• Søgaard OS, Graversen ME, Leth S, et al. The depsipeptide romidepsin reverses HIV-1 latency in vivo. PLoS Pathog. 2015;11:e1005142.
   PubMed Web of Science ®Google Scholar
• Spivak AM, Andrade A, Eisele E, et al. A pilot study assessing the safety and latency-reversing activity of disulfiram in HIV-1–infected adults on antiretroviral therapy. Clin Infect Dis Off Publ Infect Dis Soc Am. 2014;58:883–890.
   PubMed Web of Science ®Google Scholar
• Elliott JH, McMahon JH, Chang CC, et al. Short-term administration of disulfiram for reversal of latent HIV infection: a phase 2 dose-escalation study. Lancet HIV. 2015;2:e520–529.
   PubMed Web of Science ®Google Scholar
• Margolis DM, Garcia JV, Hazuda DJ, et al. Latency reversal and viral clearance to cure HIV-1. Science. 2016;353:aaf6517.
   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;517:381–385.
   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;70:1833–1842.
   PubMed Web of Science ®Google Scholar
• Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373:1627–1639.
   PubMed Web of Science ®Google Scholar
• Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–2454.
   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;458:206–210.
   PubMed Web of Science ®Google Scholar
• Finnefrock AC, Tang A, Li F, et al. PD-1 blockade in rhesus macaques: impact on chronic infection and prophylactic vaccination. J Immunol Baltim Md 1950. 2009;182:980–987.
   Google Scholar
• Bradley T, Kuraoka M, Yeh C-H, et al. Immune checkpoint modulation enhances HIV-1 antibody induction. Nat Commun. 2020;11:948.
   PubMed Web of Science ®Google Scholar
• Duraiswamy J, Kaluza KM, Freeman GJ, et al. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res. 2013;73:3591–3603.
   PubMed Web of Science ®Google Scholar
• Harper J, Gordon S, Chan CN, et al. CTLA-4 and PD-1 dual blockade induces SIV reactivation without control of rebound after antiretroviral therapy interruption. Nat Med. 2020;26:519–528.
   PubMed Web of Science ®Google Scholar
• Qin S, Xu L, Yi M, et al. Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4. Mol Cancer. 2019;18:155.
   PubMed Web of Science ®Google Scholar
• DeMuth PC, Min Y, Huang B, et al. Polymer multilayer tattooing for enhanced DNA vaccination. Nat Mater. 2013;12:367–376.
   PubMed Web of Science ®Google Scholar
• Du X, Wang J, Zhou Q, et al. Advanced physical techniques for gene delivery based on membrane perforation. Drug Deliv. 2018;25:1516–1525.
   PubMed Web of Science ®Google Scholar
• Rezaei T, Khalili S, Baradaran B, et al. Recent advances on HIV DNA vaccines development: stepwise improvements to clinical trials. J Control Release Off J Control Release Soc. 2019;316:116–137.
   PubMed Web of Science ®Google Scholar
• Cheng MA, Farmer E, Huang C, et al. Therapeutic DNA vaccines for human papillomavirus and associated diseases. Hum Gene Ther. 2018;29:971–996.
   PubMed Web of Science ®Google Scholar
• De Pooter D, Van Gulck E, Chen A, et al. A therapeutic hepatitis B virus DNA vaccine induces specific immune responses in mice and non-human primates. Vaccines (Basel). 2021;9:969.
   PubMed Web of Science ®Google Scholar
• Lopes A, Vandermeulen G, Préat V. Cancer DNA vaccines: current preclinical and clinical developments and future perspectives. J Exp Clin Cancer Res CR. 2019;38:146.
   PubMed Web of Science ®Google Scholar
• Price DA, Goulder PJ, Klenerman P, et al. Positive selection of HIV-1 cytotoxic T lymphocyte escape variants during primary infection. Proc Natl Acad Sci U S A. 1997;94:1890–1895.
   PubMed Web of Science ®Google Scholar
• Goulder PJR, Phillips RE, Colbert RA, et al. Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS. Nat Med. 1997;3:212–217.
   PubMed Web of Science ®Google Scholar
• Borrow P, Lewicki H, Wei X, et al. Antiviral pressure exerted by HIV-l-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus. Nat Med. 1997;3:205–211.
   PubMed Web of Science ®Google Scholar
• Evans DT, O’Connor DH, Jing P, et al. Virus-specific cytotoxic T-lymphocyte responses select for amino-acid variation in simian immunodeficiency virus Env and Nef. Nat Med. 1999;5:1270–1276.
   PubMed Web of Science ®Google Scholar
• Allen TM, O’Connor DH, Jing P, et al. Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia. Nature. 2000;407:386–390.
   PubMed Web of Science ®Google Scholar
• Liu Y, McNevin J, Rolland M, et al. Conserved HIV-1 epitopes continuously elicit subdominant cytotoxic T-lymphocyte responses. J Infect Dis. 2009;200:1825–1833.
   PubMed Web of Science ®Google Scholar
• Li F, Finnefrock AC, Dubey SA, et al. Mapping HIV-1 vaccine induced T-cell responses: bias towards less-conserved regions and potential impact on vaccine efficacy in the step study. PloS One. 2011;6:e20479.
   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:e60245.
   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:e86254.
   PubMed Web of Science ®Google Scholar
• Hu X, Valentin A, Rosati M, et al. HIV Env conserved element DNA vaccine alters immunodominance in Macaques. Hum Vaccines Immunother. 2017;13:2859–2871.
   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 Immunol. 2016;1600697:3999–4013.
   Google Scholar
• Fischer W, Perkins S, Theiler J, et al. Polyvalent vaccines for optimal coverage of potential T-cell epitopes in global HIV-1 variants. Nat Med. 2007;13:100–106.
   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;16:319–323.
   PubMed Web of Science ®Google Scholar
• Baden LR, Walsh SR, Seaman MS, et al. First-in-human randomized, controlled trial of mosaic HIV-1 immunogens delivered via a modified vaccinia Ankara vector. J Infect Dis. 2018;218:633–644.
   PubMed Web of Science ®Google Scholar
• Kong W-P, Wu L, Wallstrom TC, et al. Expanded breadth of the T-cell response to mosaic human immunodeficiency virus type 1 envelope DNA vaccination. J Virol. 2009;83:2201–2215.
   PubMed Web of Science ®Google Scholar
• Longo O, Tripiciano A, Fiorelli V, et al. Phase I therapeutic trial of the HIV-1 tat protein and long term follow-up. Vaccine. 2009;27:3306–3312.
   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;182:1357–1364.
   PubMed Web of Science ®Google Scholar
• Jalah R, Patel V, Kulkarni V, et al. IL-12 DNA as molecular vaccine adjuvant increases the cytotoxic T cell responses and breadth of humoral immune responses in SIV DNA vaccinated macaques. Hum Vaccines Immunother. 2012;8:1620–1629.
   PubMed Web of Science ®Google Scholar
• Kutzler MA, Wise MC, Hutnick NA, et al. Chemokine-adjuvanted electroporated DNA vaccine induces substantial protection from simian immunodeficiency virus vaginal challenge. Mucosal Immunol. 2016;9:13–23.
   PubMed Web of Science ®Google Scholar
• Øynebråten I, Hinkula J, Fredriksen AB, et al. Increased generation of HIV-1 gp120-reactive CD8+ T cells by a DNA vaccine construct encoding the chemokine CCL3. PloS One. 2014;9:e104814.
   PubMed Web of Science ®Google Scholar
• Banday AH, Jeelani S, Hruby VJ. Cancer vaccine adjuvants – recent clinical progress and future perspectives. Immunopharmacol Immunotoxicol. 2015;37:1–11.
   PubMed Web of Science ®Google Scholar
• Temizoz B, Kuroda E, Ishii KJ. Vaccine adjuvants as potential cancer immunotherapeutics. Int Immunol. 2016;28:329–338.
   PubMed Web of Science ®Google Scholar
• Matsumoto M, Tatematsu M, Nishikawa F, et al. Defined TLR3-specific adjuvant that induces NK and CTL activation without significant cytokine production in vivo. Nat Commun. 2015;6:6280.
   PubMed Web of Science ®Google Scholar
• Day CL, Kaufmann DE, Kiepiela P, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature. 2006;443:350–354.
   PubMed Web of Science ®Google Scholar
• Trautmann L, Janbazian L, Chomont N, et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med. 2006;12:1198–1202.
   PubMed Web of Science ®Google Scholar
• Petrovas C, Casazza JP, Brenchley JM, et al. PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J Exp Med. 2006;203:2281–2292.
   PubMed Web of Science ®Google Scholar
• Freeman GJ, Wherry EJ, Ahmed R, et al. Reinvigorating exhausted HIV-specific T cells via PD-1-PD-1 ligand blockade. J Exp Med. 2006;203:2223–2227.
   PubMed Web of Science ®Google Scholar
• S-j H, Mueller SN, Wherry EJ, et al. Enhancing therapeutic vaccination by blocking PD-1–mediated inhibitory signals during chronic infection. J Exp Med. 2008;205:543–555.
   PubMed Web of Science ®Google Scholar
• Soares KC, Rucki AA, Wu AA, et al. PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors. J Immunother Hagerstown Md 1997. 2015;38:1–11.
   Google Scholar
• Rahman SA, Yagnik B, Bally AP, et al. PD-1 blockade and vaccination provide therapeutic benefit against SIV by inducing broad and functional CD8+ T cells in lymphoid tissue. Sci Immunol. 2021;6:eabh3034.
   PubMed Web of Science ®Google Scholar
• Bekerman E, Hesselgesser J, Carr B, et al. PD-1 blockade and TLR7 activation lack therapeutic benefit in chronic simian immunodeficiency virus-infected macaques on antiretroviral therapy. Antimicrob Agents Chemother. 2019;63:e01163–19.
   PubMed Web of Science ®Google Scholar
• Franck CO, Fanslau L, Bistrovic Popov A, et al. Biopolymer-based carriers for DNA vaccine design. Angew Chem Int Ed Engl. 2021;60:13225–13243.
   PubMed Web of Science ®Google Scholar
• Andresen JL, Fenton OS. Nucleic acid delivery and nanoparticle design for COVID vaccines. MRS Bull. 2021;46:832–839.
   Web of Science ®Google Scholar
• Wang J, Li P, Yu Y, et al. Pulmonary surfactant-biomimetic nanoparticles potentiate heterosubtypic influenza immunity. Science. 2020;367:eaau0810.
   PubMed Web of Science ®Google Scholar
• Manrique M, Kozlowski PA, Wang S-W, et al. Nasal DNA-MVA SIV vaccination provides more significant protection from progression to AIDS than a similar intramuscular vaccination. Mucosal Immunol. 2009;2:536–550.
   PubMed Web of Science ®Google Scholar
• Huang Y, Mao K, Chen X, et al. S1P-dependent interorgan trafficking of group 2 innate lymphoid cells supports host defense. Science. 2018;359:114–119.
   PubMed Web of Science ®Google Scholar
• Wang J, Murakami T, Hakamata Y, et al. Gene gun-mediated oral mucosal transfer of interleukin 12 cDNA coupled with an irradiated melanoma vaccine in a hamster model: successful treatment of oral melanoma and distant skin lesion. Cancer Gene Ther. 2001;8:705–712.
   PubMed Web of Science ®Google Scholar
• Kichaev G, Mendoza JM, Amante D, et al. Electroporation mediated DNA vaccination directly to a mucosal surface results in improved immune responses. Hum Vaccines Immunother. 2013;9:2041–2048.
   PubMed Web of Science ®Google Scholar
• Daemen T, de Mare A, Bungener L, et al. Virosomes for antigen and DNA delivery. Adv Drug Deliv Rev. 2005;57:451–463.
   PubMed Web of Science ®Google Scholar
• Geijtenbeek TB, Kwon DS, Torensma R, et al. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell. 2000;100:587–597.
   PubMed Web of Science ®Google Scholar
• Hatziioannou T, Evans DT. Animal models for HIV/AIDS research. Nat Rev Microbiol. 2012;10:852–867.
   PubMed Web of Science ®Google Scholar
• Veazey RS, DeMaria M, Chalifoux LV, et al. Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science. 1998;280:427–431.
   PubMed Web of Science ®Google Scholar
• Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med. 2020;383:2603–2615.
   PubMed Web of Science ®Google Scholar
• Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med. 2021;384:403–416.
   PubMed Web of Science ®Google Scholar
• Fuller DH, Berglund P. Amplifying RNA vaccine development. N Engl J Med. 2020;382:2469–2471.
   PubMed Web of Science ®Google Scholar