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
Melanie Thompson, Sonya L Heath, Bentley Sweeton, Kathy Williams, Pamela Cunningham, Brandon F Keele, Sharon Sen, Brent E Palmer, Nicolas Chomont, Yongxian Xu, Rahul Basu, Michael S Hellerstein, Suefen Kwa, Harriet L Robinson, Melanie Thompson, Sonya L Heath, Bentley Sweeton, Kathy Williams, Pamela Cunningham, Brandon F Keele, Sharon Sen, Brent E Palmer, Nicolas Chomont, Yongxian Xu, Rahul Basu, Michael S Hellerstein, Suefen Kwa, Harriet L Robinson
Abstract
GV-TH-01, a Phase 1 open-label trial of a DNA prime—Modified Vaccinia Ankara (MVA) boost vaccine (GOVX-B11), was undertaken in HIV infected participants on antiretroviral treatment (ART) to evaluate safety and vaccine-elicited T cell responses, and explore the ability of elicited CD8+ T cells to control viral rebound during analytical treatment interruption (TI). Nine men who began antiretroviral therapy (ART) within 18 months of seroconversion and had sustained plasma HIV-1 RNA <50 copies/mL for at least 6 months were enrolled. Median age was 38 years, median pre-ART HIV-1 RNA was 140,000 copies/ml and mean baseline CD4 count was 755/μl. Two DNA, followed by 2 MVA, inoculations were given 8 weeks apart. Eight subjects completed all vaccinations and TI. Clinical and laboratory adverse events were generally mild, with no serious or grade 4 events. Only reactogenicity events were considered related to study drug. No treatment emergent viral resistance was seen. The vaccinations did not reduce viral reservoirs and virus re-emerged in all participants during TI, with a median time to re-emergence of 4 weeks. Eight of 9 participants had CD8+ T cells that could be stimulated by vaccine-matched Gag peptides prior to vaccination. Vaccinations boosted these responses as well as eliciting previously undetected CD8+ responses. Elicited T cells did not display signs of exhaustion. During TI, temporal patterns of viral re-emergence and Gag-specific CD8+ T cell expansion suggested that vaccine-specific CD8+ T cells had been stimulated by re-emergent virus in only 2 of 8 participants. In these 2, transient decreases in viremia were associated with Gag selection in known CD8+ T cell epitopes. We hypothesize that escape mutations, already archived in the viral reservoir, plus a poor ability of CD8+ T cells to traffic to and control virus at sites of re-emergence, limited the therapeutic efficacy of the DNA/MVA vaccine.
Trial registration: clinicaltrials.gov NCT01378156.
Conflict of interest statement
HLR is a co-founder of GeoVax, Inc., owns stock in GeoVax and is an employee of GeoVax. This does not alter her adherence to PLOS policies on sharing data and materials. YX and SK are former employees of GeoVax. RB and MSH are current employees of GeoVax. This does not alter their adherence to PLOS policies on sharing data and materials. There are no patents or pending patent applications for therapeutic immunization with this product. MT, BS, KW are employees of AIDS Research Consortium of Atlanta, which received funding from GeoVax for the conduct of the trial. SH is an employee of University of Alabama, Birmingham, which received funding from GeoVax for the conduct of the trial.
Figures
References
- Samji H, Cescon A, Hogg RS, Modur SP, Althoff KN, Buchacz K, et al. Closing the gap: increases in life expectancy among treated HIV-positive individuals in the United States and Canada. PLoS One. 2013;8(12):e81355 10.1371/journal.pone.0081355 ; PMCID: PMC3867319
- UNAIDS. How AIDS Changed Everything—MDG6: 15 years, 15 lessons of hope from the AIDS response. 2015.
- UNAIDS. Fact Sheet 2015. 2015 12/01/2015.
- Department of Health and Human Services. Panel on Antiretroviral Guidelines for Adults and Adolescents Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health andHuman Services; Available: . p. 1–239.
- Thompson MA, Aberg JA, Hoy JF, Telenti A, Benson C, Cahn P, et al. Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International Antiviral Society-USA panel. JAMA. 2012;308(4):387–402. 10.1001/jama.2012.7961
- WHO. World Health Organization, Department of HIV/AIDS & World Health Organziation. Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV. 2015 978 92 4 150956 5
- Group ISS, Lundgren JD, Babiker AG, Gordin F, Emery S, Grund B, et al. Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. N Engl J Med. 2015;373(9):795–807. 10.1056/NEJMoa1506816 ; PMCID:PMC4569751
- Goepfert PA, Elizaga ML, Seaton K, Tomaras GD, Montefiori DC, Sato A, et al. Specificity and 6-Month Durability of Immune Responses Induced by DNA and Recombinant Modified Vaccinia Ankara Vaccines Expressing HIV-1 Virus-like Particles. J Infect Dis. 2014;210(1):99–110. Epub 2014/01/10. 10.1093/infdis/jiu003 [pii]. ; PMCID:PMC4072895
- Barouch DH, Liu J, Li H, Maxfield LF, Abbink P, Lynch DM, et al. Vaccine protection against acquisition of neutralization-resistant SIV challenges in rhesus monkeys. Nature. 2012;482(7383):89–93. Epub 2012/01/06. 10.1038/nature10766 ; PMCID:PMC3271177
- Strategies for Management of Antiretroviral Therapy (SMART) Study Group, El-Sadr WM, Lundgren J, Neaton JD, Gordin F, Abrams D, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355(22):2283–96. 10.1056/NEJMoa062360
- Smith JM, Amara RR, McClure HM, Patel M, Sharma S, Yi H, et al. Multiprotein HIV-1 Clade B DNA/MVA Vaccine: Construction, Safety and Immunogenicity. AIDS Research and Human Retroviruses. 2004;20(6):654–65. 10.1089/0889222041217419
- Smith JM, Amara RR, Campbell D, Xu Y, Patel M, Sharma S, et al. DNA/MVA vaccine for HIV type 1: effects of codon-optimization and the expression of aggregates or virus-like particles on the immunogenicity of the DNA prime. AIDS Res Hum Retroviruses. 2004;20(12):1335–47. 10.1089/aid.2004.20.1335 .
- Wyatt LS, Earl PL, Liu JY, Smith JM, Montefiori DC, Robinson HL, et al. Multiprotein HIV type 1 clade B DNA and MVA vaccines: construction, expression, and immunogenicity in rodents of the MVA component. AIDS Res Hum Retroviruses. 2004;20(6):645–53. Epub 2004/07/10. 10.1089/0889222041217428
- Wyatt LS, Belyakov IM, Earl PL, Berzofsky JA, Moss B. Enhanced cell surface expression, immunogenicity and genetic stability resulting from a spontaneous truncation of HIV Env expressed by a recombinant MVA. Virology. 2008;372(2):260–72. Epub 2007/12/01. S0042-6822(07)00731-3 [pii] 10.1016/j.virol.2007.10.033 ; PMCID:PMC2289778
- Kassu A, D'Souza M, O'Connor BP, Kelly-McKnight E, Akkina R, Fontenot AP, et al. Decreased 4-1BB expression on HIV-specific CD4+ T cells is associated with sustained viral replication and reduced IL-2 production. Clin Immunol. 2009;132(2):234–45. 10.1016/j.clim.2009.03.531 ; PMCID:PMC2761838
- D'Souza M, Fontenot AP, Mack DG, Lozupone C, Dillon S, Meditz A, et al. Programmed death 1 expression on HIV-specific CD4+ T cells is driven by viral replication and associated with T cell dysfunction. J Immunol. 2007;179(3):1979–87. 10.4049/jimmunol.179.3.1979 .
- Palmer BE, Blyveis N, Fontenot AP, Wilson CC. Functional and phenotypic characterization of CD57+CD4+ T cells and their association with HIV-1-induced T cell dysfunction. J Immunol. 2005;175(12):8415–23. 10.4049/jimmunol.175.12.8415 .
- Palmer BE, Mack DG, Martin AK, Gillespie M, Mroz MM, Maier LA, et al. Up-regulation of programmed death-1 expression on beryllium-specific CD4+ T cells in chronic beryllium disease. J Immunol. 2008;180(4):2704–12. 10.4049/jimmunol.180.4.2704 ; PMCID:PMC4347847
- Vandergeeten C, Fromentin R, Merlini E, Lawani MB, DaFonseca S, Bakeman W, et al. Cross-clade ultrasensitive PCR-based assays to measure HIV persistence in large-cohort studies. J Virol. 2014;88(21):12385–96. 10.1128/JVI.00609-14 ; PMCID:PMC4248919
- Procopio FA, Fromentin R, Kulpa DA, Brehm JH, Bebin AG, Strain MC, et al. A Novel Assay to Measure the Magnitude of the Inducible Viral Reservoir in HIV-infected Individuals. EBioMedicine. 2015;2(8):872–81. 10.1016/j.ebiom.2015.06.019 ; PMCID:PMC4563128
- Keele BF, Li H, Learn GH, Hraber P, Giorgi EE, Grayson T, et al. Low-dose rectal inoculation of rhesus macaques by SIVsmE660 or SIVmac251 recapitulates human mucosal infection by HIV-1. J Exp Med. 2009;206(5):1117–34. Epub 2009/05/06. jem.20082831 [pii] 10.1084/jem.20082831 ; PMCID:PMC2715022
- Ananworanich J, Schuetz A, Vandergeeten C, Sereti I, de Souza M, Rerknimitr R, et al. Impact of multi-targeted antiretroviral treatment on gut T cell depletion and HIV reservoir seeding during acute HIV infection. PLoS One. 2012;7(3):e33948 Epub 2012/04/06. 10.1371/journal.pone.0033948 PONE-D-11-20716 [pii]. ; PMCID:PMC3316511
- Liu Z, Cumberland WG, Hultin LE, Prince HE, Detels R, Giorgi JV. Elevated CD38 antigen expression on CD8+ T cells is a stronger marker for the risk of chronic HIV disease progression to AIDS and death in the Multicenter AIDS Cohort Study than CD4+ cell count, soluble immune activation markers, or combinations of HLA-DR and CD38 expression. J Acquir Immune Defic Syndr Hum Retrovirol. 1997;16(2):83–92. 10.1097/00042560-199710010-00003 .
- Kassu A, Marcus RA, D'Souza MB, Kelly-McKnight EA, Golden-Mason L, Akkina R, et al. Regulation of virus-specific CD4+ T cell function by multiple costimulatory receptors during chronic HIV infection. J Immunol. 2010;185(5):3007–18. Epub 2010/07/27. 10.4049/jimmunol.1000156 ; PMCID:PMC3985382
- Haas DW, Gebretsadik T, Mayo G, Menon UN, Acosta EP, Shintani A, et al. Associations between CYP2B6 polymorphisms and pharmacokinetics after a single dose of nevirapine or efavirenz in African americans. J Infect Dis. 2009;199(6):872–80. 10.1086/597125 ; PMCID:PMC2784690
- Davey RT Jr., Bhat N, Yoder C, Chun TW, Metcalf JA, Dewar R, et al. HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. Proc Natl Acad Sci U S A. 1999;96(26):15109–14. 10.1073/pnas.96.26.15109 ; PMCID:PMC24781
- Garcia F, Plana M, Vidal C, Cruceta A, O'Brien WA, Pantaleo G, et al. Dynamics of viral load rebound and immunological changes after stopping effective antiretroviral therapy. AIDS. 1999;13(11):F79–86. 10.1097/00002030-199907300-00002
- Grijsen ML, Steingrover R, Wit FW, Jurriaans S, Verbon A, Brinkman K, et al. No treatment versus 24 or 60 weeks of antiretroviral treatment during primary HIV infection: the randomized Primo-SHM trial. PLoS Med. 2012;9(3):e1001196 10.1371/journal.pmed.1001196 ; PMCID:PMC3313945
- Markowitz M, Jin X, Hurley A, Simon V, Ramratnam B, Louie M, 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):634–43. 10.1086/342559
- Stohr W, Fidler S, McClure M, Weber J, Cooper D, Ramjee G, et al. Duration of HIV-1 viral suppression on cessation of antiretroviral therapy in primary infection correlates with time on therapy. PLoS One. 2013;8(10):e78287 10.1371/journal.pone.0078287 ; PMCID: PMC3808338
- Saez-Cirion A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, Girault I, Lecuroux C, et al. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLoS Pathog. 2013;9(3):e1003211 10.1371/journal.ppat.1003211 ; PMCID:PMC3597518
- Rosenberg ES, Altfeld M, Poon SH, Phillips MN, Wilkes BM, Eldridge RL, et al. Immune control of HIV-1 after early treatment of acute infection. Nature. 2000;407(6803):523–6. 10.1038/35035103
- Jacobson JM, Pat Bucy R, Spritzler J, Saag MS, Eron JJ Jr., Coombs RW, 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):623–32. Epub 2006/08/10. JID36298 [pii] 10.1086/506364 .
- Greenough TC, Cunningham CK, Muresan P, McManus M, Persaud D, Fenton T, et al. Safety and immunogenicity of recombinant poxvirus HIV-1 vaccines in young adults on highly active antiretroviral therapy. Vaccine. 2008;26(52):6883–93. Epub 2008/10/23. S0264-410X(08)01350-9 [pii] 10.1016/j.vaccine.2008.09.084 ;PMCID:PMC2845914.
- Tubiana R, Carcelain G, Vray M, Gourlain K, Dalban C, Chermak A, et al. Therapeutic immunization with a human immunodeficiency virus (HIV) type 1-recombinant canarypox vaccine in chronically HIV-infected patients: The Vacciter Study (ANRS 094). Vaccine. 2005;23(34):4292–301. Epub 2005/06/02. S0264-410X(05)00438-X [pii] 10.1016/j.vaccine.2005.04.013
- Schooley RT, Spritzler J, Wang H, Lederman MM, Havlir D, Kuritzkes DR, et al. AIDS clinical trials group 5197: a placebo-controlled trial of immunization of HIV-1-infected persons with a replication-deficient adenovirus type 5 vaccine expressing the HIV-1 core protein. J Infect Dis. 202(5):705–16. Epub 2010/07/29. 10.1086/655468 ; PMCID:PMC2916952
- Casazza JP, Bowman KA, Adzaku S, Smith EC, Enama ME, Bailer RT, et al. Therapeutic vaccination expands and improves the function of the HIV-specific memory T-cell repertoire. J Infect Dis. 2013;207(12):1829–40. 10.1093/infdis/jit098 ; PMCID:PMC3654747
- Gomez CE, Perdiguero B, Garcia-Arriaza J, Cepeda V, Sanchez-Sorzano CO, Mothe B, et al. A Phase I Randomized Therapeutic MVA-B Vaccination Improves the Magnitude and Quality of the T Cell Immune Responses in HIV-1-Infected Subjects on HAART. PLoS One. 2015;10(11):e0141456 10.1371/journal.pone.0141456 ; PMCID:PMC4636254
- Garcia F, Climent N, Guardo AC, Gil C, Leon A, Autran B, et al. A dendritic cell-based vaccine elicits T cell responses associated with control of HIV-1 replication. Sci Transl Med. 2013;5(166):166ra2 Epub 2013/01/04. 10.1126/scitranslmed.3004682 5/166/166ra2 [pii]. .
- Autran B, Murphy RL, Costagliola D, Tubiana R, Clotet B, Gatell J, 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):1313–22. Epub 2008/06/27. 0.1097/QAD.0b013e3282fdce9400002030-200807110-00009 [pii]. 10.1097/QAD.0b013e3282fdce94
- Wherry EJ, Blattman JN, Murali-Krishna K, van der Most R, Ahmed R. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol. 2003;77(8):4911–27. 10.1128/jvi.77.8.4911-4927.2003
- Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature. 2006;443(7109):350–4. Epub 2006/08/22. 10.1038/nature05115
- Jin HT, Anderson AC, Tan WG, West EE, Ha SJ, Araki K, et al. Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proc Natl Acad Sci U S A. 2010;107(33):14733–8. 10.1073/pnas.1009731107
- Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A, et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol. 2009;10(1):29–37. 10.1038/ni.1679 ; PMCID:PMC2605166
- Connick E, Mattila T, Folkvord JM, Schlichtemeier R, Meditz AL, Ray MG, et al. CTL fail to accumulate at sites of HIV-1 replication in lymphoid tissue. J Immunol. 2007;178(11):6975–83. 10.4049/jimmunol.178.11.6975 Epub 2007/05/22. 178/11/6975 [pii].
- Folkvord JM, Armon C, Connick E. Lymphoid follicles are sites of heightened human immunodeficiency virus type 1 (HIV-1) replication and reduced antiretroviral effector mechanisms. AIDS Res Hum Retroviruses. 2005;21(5):363–70. Epub 2005/06/03. 10.1089/aid.2005.21.363
- Fukazawa Y, Park H, Cameron MJ, Lefebvre F, Lum R, Coombes N, et al. Lymph node T cell responses predict the efficacy of live attenuated SIV vaccines. Nat Med. 2012;18(11):1673–81. Epub 2012/09/11. 10.1038/nm.2934 nm.2934 [pii]. ; PMCID:PMC3493820
- Koup RA. Virus escape from CTL recognition. J Exp Med. 1994;180(3):779–82. 10.1084/jem.180.3.779 ; PMCID:PMC2191640.
- Borrow P, Lewicki H, Wei X, Horwitz MS, Peffer N, Meyers H, et al. Antiviral pressure exerted by HIV-1-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus. Nature Medicine. 1997;3(2):205–11. 10.1038/nm0297-205
- Goonetilleke N, Liu MK, Salazar-Gonzalez JF, Ferrari G, Giorgi E, Ganusov VV, et al. The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection. J Exp Med. 2009;206(6):1253–72. 10.1084/jem.20090365 ; PMCID:PMC2715063
- Deng K, Pertea M, Rongvaux A, Wang L, Durand CM, Ghiaur G, et al. Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations. Nature. 2015;517(7534):381–5. Epub 2015/01/07. 10.1038/nature14053 nature14053 [pii]. ; PMCID:PMC4406054
- Murali-Krishna K, Altman JD, Suresh M, Sourdive DJ, Zajac AJ, Miller JD, et al. Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. Immunity. 1998;8(2):177–87. 10.1016/s1074-7613(00)80470-7
- Miller JD, van der Most RG, Akondy RS, Glidewell JT, Albott S, Masopust D, et al. Human effector and memory CD8+ T cell responses to smallpox and yellow fever vaccines. Immunity. 2008;28(5):710–22. Epub 2008/05/13. 10.1016/j.immuni.2008.02.020 S1074-7613(08)00194-5 [pii].
- Garde D. Argos tanks as its HIV immunotherapy flunks Phase II FierceBiotech. 2015.
- Gunthard HF, Wong JK, Spina CA, Ignacio C, Kwok S, Christopherson C, et al. Effect of influenza vaccination on viral replication and immune response in persons infected with human immunodeficiency virus receiving potent antiretroviral therapy. J Infect Dis. 2000;181(2):522–31. 10.1086/315260
- Staprans SI, Hamilton BL, Follansbee SE, Elbeik T, Barbosa P, Grant RM, et al. Activation of virus replication after vaccination of HIV-1-infected individuals. J Exp Med. 1995;182(6):1727–37. 10.1084/jem.182.6.1727 ; PMCID:PMC2192265.
- Tasker SA, O'Brien WA, Treanor JJ, Weiss PJ, Olson PE, Kaplan AH, et al. Effects of influenza vaccination in HIV-infected adults: a double-blind, placebo-controlled trial. Vaccine. 1998;16(9–10):1039–42. 10.1016/s0264-410x(97)00275-2 .
- Winckelmann AA, Munk-Petersen LV, Rasmussen TA, Melchjorsen J, Hjelholt TJ, Montefiori D, et al. Administration of a Toll-Like Receptor 9 Agonist Decreases the Proviral Reservoir in Virologically Suppressed HIV-Infected Patients. PLoS One. 2013;8(4):e62074 Epub 2013/05/03. 10.1371/journal.pone.0062074 PONE-D-12-38578 [pii]. ; PMCID:PMC3637371
- Scheller C, Ullrich A, McPherson K, Hefele B, Knoferle J, Lamla S, et al. CpG oligodeoxynucleotides activate HIV replication in latently infected human T cells. J Biol Chem. 2004;279(21):21897–902. Epub 2004/03/16. 10.1074/jbc.M311609200 M311609200 [pii].
- Suschak JJ, Wang S, Fitzgerald KA, Lu S. A cGAS-Independent STING/IRF7 Pathway Mediates the Immunogenicity of DNA Vaccines. J Immunol. 2015. 10.4049/jimmunol.1501836 ; PMCID:PMC4685033
- Hansen SG, Sacha JB, Hughes CM, Ford JC, Burwitz BJ, Scholz I, et al. Cytomegalovirus vectors violate CD8+ T cell epitope recognition paradigms. Science. 2013;340(6135):1237874 Epub 2013/05/25. 10.1126/science.1237874 340/6135/1237874 [pii]. ; PMCID:PMC3816976
Source: PubMed