, Volume 23, Issue 3, pp 137–153 | Cite as

Progress on the Induction of Neutralizing Antibodies Against HIV Type 1 (HIV-1)

Leading Article


Infection with HIV type 1 (HIV-1), the causative agent of AIDS, is one of the most catastrophic pandemics to affect human healthcare in the latter 20th century. The best hope of controlling this pandemic is the development of a successful prophylactic vaccine. However, to date, this goal has proven to be exceptionally elusive. The recent failure of an experimental vaccine in a phase IIb study, named the STEP trial, intended solely to elicit cell-mediated immune responses against HIV-1, has highlighted the need for a balanced immune response consisting of not only cellular immunity but also a broad and potent humoral antibody response that can prevent infection with HIV-1. This article reviews the efforts made up to this point to elicit such antibody responses, especially with regard to the use of a DNA prime-protein boost regimen, which has been proven to be a highly effective platform for the induction of neutralizing antibodies in both animal and early-phase human studies.



This work was supported in part by US National Institutes of Health (NIH) research grants R29AI40337 and R01AI65250 to Shan Lu. Michael Vaine was supported by NIH training grant 5 T32 AIO7349-18. The authors have no other affiliations or financial involvement with any organization or entity with a financial interest or conflict with the subject matter or materials discussed in this manuscript, apart from those disclosed.


  1. 1.
    UNAIDS/WHO. Global AIDS epidemic continues to grow 2006 [online]. Available from URL: [Accessed 2009 Apr 29]
  2. 2.
    Flynn NM, Forthal DN, Harro CD, et al. Placebo-controlled phase 3 trial of a recombinant glycoprotein 120 vaccine to prevent HIV-1 infection. J Infect Dis 2005 Mar 1; 191(5): 654–65PubMedCrossRefGoogle Scholar
  3. 3.
    Pitisuttithum P, Gilbert P, Gurwith M, et al. Randomized, double-blind, placebo-controlled efficacy trial of a bivalent recombinant glycoprotein 120 HIV-1 vaccine among injection drug users in Bangkok, Thailand. J Infect Dis 2006 Dec 15; 194(12): 1661–71PubMedCrossRefGoogle Scholar
  4. 4.
    Buchbinder SP, Mehrotra DV, Duerr A, et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet 2008; 372: 1881–93PubMedCrossRefGoogle Scholar
  5. 5.
    Borrow P, Lewicki H, Hahn BH, et al. Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J Virol 1994 Sep; 68(9): 6103–10PubMedGoogle Scholar
  6. 6.
    Koup RA, Safrit JT, Cao Y, et al. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol 1994 Jul; 68(7): 4650–5PubMedGoogle Scholar
  7. 7.
    Schmitz JE, Kuroda MJ, Santra S, et al. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 1999 Feb 5; 283(5403): 857–60PubMedCrossRefGoogle Scholar
  8. 8.
    Bernard NF, Pederson K, Chung F, et al. HIV-specific cytotoxic T-lymphocyte activity in immunologically normal HIV-infected persons. AIDS 1998 Nov 12; 12(16): 2125–39PubMedCrossRefGoogle Scholar
  9. 9.
    Pontesilli O, Klein MR, Kerkhof-Garde SR, et al. Longitudinal analysis of human immunodeficiency virus type 1-specific cytotoxic T lymphocyte responses: a predominant gag-specific response is associated with non-progressive infection. J Infect Dis 1998 Oct; 178(4): 1008–18PubMedCrossRefGoogle Scholar
  10. 10.
    Amara RR, Villinger F, Altman JD, et al. Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA/MVA vaccine. Science 2001 Apr 6; 292(5514): 69–74PubMedCrossRefGoogle Scholar
  11. 11.
    Shiver JW, Fu TM, Chen L, et al. Replication-incompetent adenoviral vaccine vector elicits effective anti-immunodeficiency-virus immunity. Nature 2002 Jan 17; 415(6869): 331–5PubMedCrossRefGoogle Scholar
  12. 12.
    Barouch DH, Santra S, Schmitz JE, et al. Control of viremia and prevention of clinical AIDS in rhesus monkeys by cytokine-augumented DNA vaccination. Science 2000 Oct 20; 290: 486–92PubMedCrossRefGoogle Scholar
  13. 13.
    Casimiro D, Wang F, Schleif W, et al. Attenuation of simian immunodeficiency virus SIVmac239 infection by prophylactic immunization with dna and recombinant adenoviral vaccine vectors expressing Gag. J Virol 2005; 79(24): 15547–55PubMedCrossRefGoogle Scholar
  14. 14.
    Liang X, Casimiro DR, Schleif WA, et al. Vectored Gag and Env but not Tat show efficacy against simian-human immunodeficiency virus 89.6P challenge in Mamu-A*01-negative rhesus monkeys. J Virol 2005 Oct; 79(19): 12321–31PubMedCrossRefGoogle Scholar
  15. 15.
    HIV vaccine failure prompts Merck to halt trial. Nature 2007 Sep 27; 449(7161): 390Google Scholar
  16. 16.
    Steinbrook R. One step forward, two steps back: will there ever be an AIDS vaccine? N Engl J Med 2007 Dec 27; 357(26): 2653–5PubMedCrossRefGoogle Scholar
  17. 17.
    Pantaleo G. HIV-1 T-cell vaccines: evaluating the next step. Lancet Infect Dis 2008 Feb; 8(2): 82–3PubMedCrossRefGoogle Scholar
  18. 18.
    Ledford H. HIV vaccine may raise risk. Nature 2007 Nov 15; 450(7168): 325PubMedCrossRefGoogle Scholar
  19. 19.
    Korber B, Gaschen B, Yusim K, et al. Evolutionary and immunological implications of contemporary HIV-1 variation. Br Med Bull 2001; 58: 19–42PubMedCrossRefGoogle Scholar
  20. 20.
    Pantophlet R, Burton DR. GP120: target for neutralizing HIV-1 antibodies. Annu Rev Immunol 2006; 24: 739–69PubMedCrossRefGoogle Scholar
  21. 21.
    Burton DR, Stanfield RL, Wilson IA. Antibody vs HIV in a clash of evolutionary titans. Proc Natl Acad Sci U S A 2005 Oct 18; 102(42): 14943–8PubMedCrossRefGoogle Scholar
  22. 22.
    Conley AJ, Kessler II JA, Boots LJ, et al. The consequence of passive administration of an anti-human immunodeficiency virus type 1 neutralizing monoclonal antibody before challenge of chimpanzees with a primary virus isolate. J Virol 1996 Oct; 70(10): 6751–8PubMedGoogle Scholar
  23. 23.
    Emini EA, Schleif WA, Nunberg JH, et al. Prevention of HIV-1 infection in chimpanzees by gp120 V3 domain-specific monoclonal antibody. Nature 1992 Feb 20; 355(6362): 728–30PubMedCrossRefGoogle Scholar
  24. 24.
    Hofmann-Lehmann R, Vlasak J, Rasmussen RA, et al. Postnatal pre- and postexposure passive immunization strategies: protection of neonatal macaques against oral simian-human immunodeficiency virus challenge. J Med Primatol 2002 Jun; 31(3): 109–19PubMedCrossRefGoogle Scholar
  25. 25.
    Hofmann-Lehmann R, Vlasak J, Rasmussen RA, et al. Postnatal passive immunization of neonatal macaques with a triple combination of human monoclonal antibodies against oral simian-human immunodeficiency virus challenge. J Virol 2001 Aug; 75(16): 7470–80PubMedCrossRefGoogle Scholar
  26. 26.
    Mascola JR, Lewis MG, Stiegler G, et al. Protection of Macaques against pathogenic simian/human immunodeficiency virus 89.6PD by passive transfer of neutralizing antibodies. J Virol 1999 May; 73(5): 4009–18PubMedGoogle Scholar
  27. 27.
    Mascola JR, Stiegler G, VanCott TC, et al. Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV chimeric virus by passive infusion of neutralizing antibodies. Nat Med 2000 Feb; 6(2): 207–10PubMedCrossRefGoogle Scholar
  28. 28.
    Berman PW, Gregory TJ, Riddle L, et al. Protection of chimpanzees from infection by HIV-1 after vaccination with recombinant glycoprotein gp120 but not gp160. Nature 1990 Jun 14; 345(6276): 622–5PubMedCrossRefGoogle Scholar
  29. 29.
    el-Amad Z, Murthy KK, Higgins K, et al. Resistance of chimpanzees immunized with recombinant gp120SF2 to challenge by HIV-1SF2. AIDS 1995 Dec; 9(12): 1313–22PubMedCrossRefGoogle Scholar
  30. 30.
    Berman PW, Murthy KK, Wrin T, et al. Protection of MN-rgp120-immunized chimpanzees from heterologous infection with a primary isolate of human immunodeficiency virus type 1. J Infect Dis 1996 Jan; 173(1): 52–9PubMedCrossRefGoogle Scholar
  31. 31.
    Schwartz DH, Gorse G, Clements ML, et al. Induction of HIV-1-neutralising and syncytium-inhibiting antibodies in uninfected recipients of HIV-1IIIB rgp120 subunit vaccine. Lancet 1993 Jul 10; 342(8863): 69–73PubMedCrossRefGoogle Scholar
  32. 32.
    Belshe RB, Clements ML, Dolin R, et al. Safety and immunogenicity of a fully glycosylated recombinant gp160 human immunodeficiency virus type 1 vaccine in subjects at low risk of infection. National Institute of Allergy and Infectious Diseases AIDS Vaccine Evaluation Group Network. J Infect Dis 1993 Dec; 168(6): 1387–95PubMedCrossRefGoogle Scholar
  33. 33.
    Belshe RB, Graham BS, Keefer MC, et al. Neutralizing antibodies to HIV-1 in seronegative volunteers immunized with recombinant gp120 from the MN strain of HIV-1. NIAID AIDS Vaccine Clinical Trials Network. JAMA 1994 Aug 10; 272(6): 475–80PubMedCrossRefGoogle Scholar
  34. 34.
    Graham BS, Keefer MC, McElrath MJ, et al. Safety and immunogenicity of a candidate HIV-1 vaccine in healthy adults: recombinant glycoprotein (rgp) 120: a randomized, double-blind trial. NIAID AIDS Vaccine Evaluation Group. Ann Intern Med 1996 Aug 15; 125(4): 270–9PubMedGoogle Scholar
  35. 35.
    Pitisuttithum P, Berman PW, Phonrat B, et al. Phase I/II study of a candidate vaccine designed against the B and E subtypes of HIV-1. J Acquir Immune Defic Syndr 2004 Sep 1; 37(1): 1160–5PubMedCrossRefGoogle Scholar
  36. 36.
    Francis DP, Gregory T, McElrath MJ, et al. Advancing AIDSVAX to phase 3: safety, immunogenicity, and plans for phase 3. AIDS Res Hum Retroviruses 1998 Oct; 14Suppl. 3: S325–31PubMedGoogle Scholar
  37. 37.
    Gilbert PB, Peterson ML, Follmann D, et al. Correlation between immunologic responses to a recombinant glycoprotein 120 vaccine and incidence of HIV-1 infection in a phase 3 HIV-1 preventive vaccine trial. J Infect Dis 2005 Mar 1; 191(5): 666–77PubMedCrossRefGoogle Scholar
  38. 38.
    Gao F, Weaver EA, Lu Z, et al. Antigenicity and immunogenicity of a synthetic human immunodeficiency virus type 1 group M consensus envelope glycoprotein. J Virol 2005 Jan 2005; 79(2): 1154–63PubMedCrossRefGoogle Scholar
  39. 39.
    Liao HX, Sutherland LL, Xia SM, et al. A group M consensus envelope glycoprotein induces antibodies that neutralize subsets of subtype B and C HIV-1 primary viruses. Virology 2006 Sep 30; 353(2): 268–82PubMedCrossRefGoogle Scholar
  40. 40.
    Kothe DL, Decker JM, Li Y, et al. Antigenicity and immunogenicity of HIV-1 consensus subtype B envelope glycoproteins. Virology 2007 Mar 30; 360(1): 218–34PubMedCrossRefGoogle Scholar
  41. 41.
    Kothe DL, Li Y, Decker JM, et al. Ancestral and consensus envelope immunogens for HIV-1 subtype C. Virology2006 Sep 1; 352 (2): 438–49Google Scholar
  42. 42.
    Doria-Rose NA, Learn GH, Rodrigo AG, et al. Human immunodeficiency virus type 1 subtype B ancestral envelope protein is functional and elicits neutralizing antibodies in rabbits similar to those elicited by a circulating subtype B envelope. J Virol 2005 Sep; 79(17): 11214–24PubMedCrossRefGoogle Scholar
  43. 43.
    Lu S, Wyatt R, Richmond JF, et al. Immunogenicity of DNA vaccines expressing human immunodeficiency virus type 1 envelope glycoprotein with and without deletions in the V1/2 and V3 regions. AIDS Res Hum Retroviruses 1998; 14(2): 151–5PubMedCrossRefGoogle Scholar
  44. 44.
    Derby NR, Kraft Z, Kan E, et al. Antibody responses elicited in macaques immunized with human immunodeficiency virus type 1 (HIV-1) SF162-derived gp 140 envelope immunogens: comparison with those elicited during homologous simian/human immunodeficiency virus SHIVSF162P4 and heterologous HIV-1 infection. J Virol 2006 Sep; 80(17): 8745–62PubMedCrossRefGoogle Scholar
  45. 45.
    Kim YB, Han DP, Cao C, et al. Immunogenicity and ability of variable loop-deleted human immunodeficiency virus type 1 envelope glycoproteins to elicit neutralizing antibodies. Virology 2003 Jan 5; 305(1): 124–37PubMedCrossRefGoogle Scholar
  46. 46.
    Barnett SW, Lu S, Srivastava I, et al. The ability of an oligomeric human immunodeficiency virus type 1 (HIV-1) envelope antigen to elicit neutralizing antibodies against primary HIV-1 isolates is improved following partial deletion of the second hypervariable region. J Virol 2001 Jun; 75(12): 5526–40PubMedCrossRefGoogle Scholar
  47. 47.
    Lian Y, Srivastava I, Gomez-Roman VR, et al. Evaluation of envelope vaccines derived from the South African subtype C human immunodeficiency virus type 1 TV1 strain. J Virol 2005 Nov; 79(21): 13338–49PubMedCrossRefGoogle Scholar
  48. 48.
    Srivastava IK, Stamatatos L, Kan E, et al. Purification, characterization, and immunogenicity of a soluble trimeric envelope protein containing a partial deletion of the V2 loop derived from SF162, an R5-tropic human immunodeficiency virus type 1 isolate. J Virol 2003 Oct; 77(20): 11244–59PubMedCrossRefGoogle Scholar
  49. 49.
    Selvarajah S, Puffer B, Pantophlet R, et al. Comparing antigenicity and immunogenicity of engineered gp120. J Virol 2005 Oct; 79(19): 12148–63PubMedCrossRefGoogle Scholar
  50. 50.
    Selvarajah S, Puffer BA, Lee FH, et al. Focused dampening of antibody response to the immunodominant variable loops by engineered soluble gp140. AIDS Res Hum Retroviruses 2008 Feb; 24(2): 301–14PubMedCrossRefGoogle Scholar
  51. 51.
    Reitter JN, Means RE, Desrosiers RC. A role for carbohydrates in immune evasion in AIDS. Nat Med 1998 Jun; 4(6): 679–84PubMedCrossRefGoogle Scholar
  52. 52.
    Li Y, Cleveland B, Klots I, et al. Removal of a single N-linked glycan in human immunodeficiency virus type 1 gp120 results in an enhanced ability to induce neutralizing antibody responses. J Virol 2008 Jan; 82(2): 638–51PubMedCrossRefGoogle Scholar
  53. 53.
    Bolmstedt A, Sjolander S, Hansen JE, et al. Influence of N-linked glycans in V4–V5 region of human immunodeficiency virus type 1 glycoprotein gp160 on induction of a virus-neutralizing humoral response. J Acquir Immune Defic Syndr Hum Retrovirol 1996 Jul; 12(3): 213–20PubMedCrossRefGoogle Scholar
  54. 54.
    Quinones-Kochs MI, Buonocore L, Rose JK. Role of N-linked glycans in a human immunodeficiency virus envelope glycoprotein: effects on protein function and the neutralizing antibody response. J Virol 2002 May; 76(9): 4199–211PubMedCrossRefGoogle Scholar
  55. 55.
    Earl PL, Sugiura W, Montefiori DC, et al. Immunogenicity and protective efficacy of oligomeric human immunodeficiency virus type 1 gp140. J Virol 2001 Jan; 75(2): 645–53PubMedCrossRefGoogle Scholar
  56. 56.
    Zhang PF, Cham F, Dong M, et al. Extensively cross-reactive anti-HIV-1 neutralizing antibodies induced by gp140 immunization. Proc Natl Acad Sci U S A2007 Jun 12; 104(24): 10193–8PubMedCrossRefGoogle Scholar
  57. 57.
    Beddows S, Schulke N, Kirschner M, et al. Evaluating the immunogenicity of a disulfide-stabilized, cleaved, trimeric form of the envelope glycoprotein complex of human immunodeficiency virus type 1. J Virol 2005 Jul; 79(14): 8812–27PubMedCrossRefGoogle Scholar
  58. 58.
    Yang X, Wyatt R, Sodroski J. Improved elicitation of neutralizing antibodies against primary human immunodeficiency viruses by soluble stabilized envelope glycoprotein trimers. J Virol 2001 Feb; 75(3): 1165–71PubMedCrossRefGoogle Scholar
  59. 59.
    Li Y, Svehla K, Mathy NL, et al. Characterization of antibody responses elicited by human immunodeficiency virus type 1 primary isolate trimeric and monomeric envelope glycoproteins in selected adjuvants. J Virol 2006 Feb; 80(3): 1414–26PubMedCrossRefGoogle Scholar
  60. 60.
    Dey B, Pancera M, Svehla K, et al. Characterization of human immunodeficiency virus type 1 monomeric and trimeric gp120 glycoproteins stabilized in the CD4-bound state: antigenicity, biophysics, and immunogenicity. J Virol 2007 Jun; 81(11): 5579–93PubMedCrossRefGoogle Scholar
  61. 61.
    Liang X, Munshi S, Shendure J, et al. Epitope insertion into variable loops of HIV-1 gp120 as a potential means to improve immunogenicity of viral envelope protein. Vaccine 1999; 17: 2862–72PubMedCrossRefGoogle Scholar
  62. 62.
    Law M, Cardoso RM, Wilson IA, et al. Antigenic and immunogenic study of membrane-proximal external region-grafted gp120 antigens by a DNA prime-protein boost immunization strategy. J Virol 2007 Apr; 81(8): 4272–85PubMedCrossRefGoogle Scholar
  63. 63.
    Mascola JR, D’Souza P, Gilbert P, et al. Recommendations for the design and use of standard virus panels to assess neutralizing antibody responses elicited by candidate human immunodeficiency virus type 1 vaccines. J Virol 2005 Aug; 79(16): 10103–7PubMedCrossRefGoogle Scholar
  64. 64.
    Li M, Gao F, Mascola R, et al. Human immunodeficiency virus type 1 Env clones from acute and early subtype B infections for standardized assessments of vaccine-elicited neutralizing antibodies. J Virol 2005 Aug; 79(16): 10108–25PubMedCrossRefGoogle Scholar
  65. 65.
    Stamatatos L, Cheng-Mayer C. An envelope modification that renders a primary, neutralization-resistant clade B human immunodeficiency virus type 1 isolate highly susceptible to neutralization by sera from other clades. J Virol 1998 Oct; 72(10): 7840–5PubMedGoogle Scholar
  66. 66.
    Pinter A, Honnen WJ, He Y, et al. The V1/V2 domain of gp120 is a global regulator of the sensitivity of primary human immunodeficiency virus type 1 isolates to neutralization by antibodies commonly induced upon infection. J Virol 2004 May; 78(10): 5205–15PubMedCrossRefGoogle Scholar
  67. 67.
    Johnson WE, Sanford H, Schwall L, et al. Assorted mutations in the envelope gene of simian immunodeficiency virus lead to loss of neutralization resistance against antibodies representing a broad spectrum of specificities. J Virol 2003 Sep; 77(18): 9993–10003PubMedCrossRefGoogle Scholar
  68. 68.
    Cao J, Sullivan N, Desjardin E, et al. Replication and neutralization of human immunodeficiency virus type 1 lacking the V1 and V2 variable loops of the gp120 envelope glycoprotein. J Virol 1997 Dec; 71(12): 9808–12PubMedGoogle Scholar
  69. 69.
    Srivastava IK, VanDorsten K, Vojtech L, et al. Changes in the immunogenic properties of soluble gp 140 human immunodeficiency virus envelope constructs upon partial deletion of the second hypervariable region. J Virol 2003 Feb; 77(4): 2310–20PubMedCrossRefGoogle Scholar
  70. 70.
    Back NK, Smit L, De Jong J, et al. An N-glycan within the human immunodeficiency virus type 1 gp120 V3 loop affects virus neutralization. Virology 1994 Mar; 199(2): 431–8PubMedCrossRefGoogle Scholar
  71. 71.
    Kang SM, Quan FS, Huang C, et al. Modified HIV envelope proteins with enhanced binding to neutralizing monoclonal antibodies. Virology 2005 Jan 5; 331(1): 20–32PubMedCrossRefGoogle Scholar
  72. 72.
    McCaffrey RA, Saunders C, Hensel M, et al. N-linked glycosylation of the V3 loop and the immunologically silent face of gp120 protects human immunodeficiency virus type 1 SF162 from neutralization by anti-gp120 and anti-gp41 antibodies. J Virol 2004 Apr; 78(7): 3279–95PubMedCrossRefGoogle Scholar
  73. 73.
    Reynard F, Fatmi A, Verrier B, et al. HIV-1 acute infection Env glycomutants designed from 3D model: effects on processing, antigenicity, and neutralization sensitivity. Virology 2004 Jun 20; 324(1): 90–102PubMedCrossRefGoogle Scholar
  74. 74.
    Koch M, Pancera M, Kwong PD, et al. Structure-based, targeted deglycosylation of HIV-1 gp120 and effects on neutralization sensitivity and antibody recognition. Virology 2003 Sep 1; 313(2): 387–400PubMedCrossRefGoogle Scholar
  75. 75.
    Huang Z, Chou A, Tanguay J, et al. Levels of N-linked glycosylation on the V1 loop of HIV-1 Env proteins and their relationship to the antigenicity of Env from primary viral isolates. Curr HIV Res 2008 Jun; 6(4): 296–305PubMedCrossRefGoogle Scholar
  76. 76.
    Pantophlet R, Wilson IA, Burton DR. Hyperglycosylated mutants of human immunodeficiency virus (HIV) type 1 monomeric gp120 as novel antigens for HIV vaccine design. J Virol 2003 May; 77(10): 5889–901PubMedCrossRefGoogle Scholar
  77. 77.
    Pancera M, Lebowitz J, Schon A, et al. Soluble mimetics of human immunodeficiency virus type 1 viral spikes produced by replacement of the native trimerization domain with a heterologous trimerization motif: characterization and ligand binding analysis. J Virol 2005 Aug; 79(15): 9954–69PubMedCrossRefGoogle Scholar
  78. 78.
    Binley JM, Sanders RW, Clas B, et al. A Recombinant human immunodeficiency virus type 1 envelope glycoprotein complex stabilized by an intermolecular disulfide bond between the gp120 and gp41 subunits is an antigenic mimic of the trimeric virion-associated structure. J Virol 2000; 74(2): 627–43PubMedCrossRefGoogle Scholar
  79. 79.
    Sanders RW, Vesanen M, Schuelke N, et al. Stabilization of the soluble, cleaved, trimeric form of the envelope glycoprotein complex of human immunodeficiency virus type 1. J Virol 2002 Sep; 76(17): 8875–89PubMedCrossRefGoogle Scholar
  80. 80.
    Beddows S, Franti M, Dey AK,et al. A comparative immunogenicity study in rabbits of disulfide-stabilized, proteolytically cleaved, soluble trimeric human immunodeficiency virus type 1 gp140, trimeric cleavage-defective gp140 and monomeric gp120. Virology 2007; 360: 329–40PubMedCrossRefGoogle Scholar
  81. 81.
    Burioni R, Mancini N, De Marco D, et al. Anti-HIV-1 response elicited in rabbits by anti-idiotype monoclonal antibodies mimicking the CD4-binding site. PLoS ONE 2008; 3(10): e3423PubMedCrossRefGoogle Scholar
  82. 82.
    Catanzaro AT, Koup RA, Roederer M, et al. Phase 1 safety and immunogenicity evaluation of a multiclade HIV-1 candidate vaccine delivered by a replication-defective recombinant adenovirus vector. J Infect Dis 2006 Dec 15; 194(12): 1638–49PubMedCrossRefGoogle Scholar
  83. 83.
    Russell ND, Graham BS, Keefer MC, et al. Phase 2 study of an HIV-1 canarypox vaccine (vCP1452) alone and in combination with rgp120: negative results fail to trigger a phase 3 correlates trial. J Acquir Immune Defic Syndr 2007 Feb 1; 44(2): 203–12PubMedCrossRefGoogle Scholar
  84. 84.
    Catanzaro AT, Roederer M, Koup RA, et al. Phase I clinical evaluation of a six-plasmid multiclade HIV-1 DNA candidate vaccine. Vaccine 2007 May 16; 25(20): 4085–92PubMedCrossRefGoogle Scholar
  85. 85.
    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 Dec 15; 194(12): 1650–60PubMedCrossRefGoogle Scholar
  86. 86.
    Mulligan MJ, Russell ND, Celum C, et al. Excellent safety and tolerability of the human immunodeficiency virus type 1 pGA2/JS2 plasmid DNA priming vector vaccine in HIV type 1 uninfected adults. AIDS Res Hum Retroviruses 2006 Jul; 22(7): 678–83PubMedCrossRefGoogle Scholar
  87. 87.
    Mascola JR, Sambor A, Beaudry K, et al. Neutralizing antibodies elicited by immunization of monkeys with DNA plasmids and recombinant adenoviral vectors expressing human immunodeficiency virus type 1 proteins. J Virol 2005 Jan; 79(2): 771–9PubMedCrossRefGoogle Scholar
  88. 88.
    Wang S, Kennedy JS, West K, et al. Cross-subtype antibody and cellular immune responses induced by a polyvalent DNA prime-protein boost HIV-1 vaccine in healthy human volunteers. Vaccine 2008; 26: 3947–57PubMedCrossRefGoogle Scholar
  89. 89.
    Gupta K, Hudgens M, Corey L, et al. Safety and immunogenicity of a high-titered canarypox vaccine in combination with rgp120 in a diverse population of HIV-1-uninfected adults: AIDS Vaccine Evaluation Group Protocol 022A. J Acquir Immune Defic Syndr 2002 Mar 1; 29(3): 254–61PubMedGoogle Scholar
  90. 90.
    Thongcharoen P, Suriyanon V, Paris RM, et al. A phase 1/2 comparative vaccine trial of the safety and immunogenicity of a CRF01_AE (subtype E) candidate vaccine: ALVAC-HIV (vCP1521) prime with oligomeric gp160 (92TH023/LAI-DID) or bivalent gp120 (CM235/SF2) boost. J Acquir Immune Defic Syndr 2007 Sep 1; 46(1): 48–55PubMedGoogle Scholar
  91. 91.
    Evans TG, Keefer MC, Weinhold KJ, et al. A canarypox vaccine expressing multiple human immunodeficiency virus type 1 genes given alone or with rgp120 elicits broad and durable CD8+ cytotoxic T lymphocyte responses in seronegative volunteers. J Infect Dis 1999 Aug; 180(2): 290–8PubMedCrossRefGoogle Scholar
  92. 92.
    Belshe RB, Stevens C, Gorse GJ, et al. Safety and immunogenicity of a canarypox-vectored human immunodeficiency virus type 1 vaccine with or without gp120: a phase 2 study in higher- and lower-risk volunteers. J Infect Dis 2001 May 1; 183(9): 1343–52PubMedCrossRefGoogle Scholar
  93. 93.
    Chakrabarti BK, Kong WP, Wu BY, et al. Modifications of the human immunodeficiency virus envelope glycoprotein enhance immunogenicity for genetic immunization. J Virol 2002 Jun; 76(11): 5357–68PubMedCrossRefGoogle Scholar
  94. 94.
    Seaman MS, Xu L, Beaudry K, et al. Multiclade human immunodeficiency virus type 1 envelope immunogens elicit broad cellular and humoral immunity in rhesus monkeys. J Virol 2005 Mar; 79(5): 2956–63PubMedCrossRefGoogle Scholar
  95. 95.
    Seaman MS, Leblanc DF, Grandpre LE, et al. Standardized assessment of NAb responses elicited in rhesus monkeys immunized with single- or multiclade HIV-1 envelope immunogens. Virology 2007; 367: 175–86PubMedCrossRefGoogle Scholar
  96. 96.
    Wang B, Ugen KE, Srikantan V, et al. Gene inoculation generates immune responses against human immunodeficiency virus type 1. Proc Natl Acad Sci U S A 1993 May 1; 90(9): 4156–60PubMedCrossRefGoogle Scholar
  97. 97.
    Lu S, Santoro JC, Fuller DH, et al. Use of DNAs expressing HIV-1 Env and noninfectious HIV-1 particles to raise antibody responses in mice. Virology 1995; 209(1): 147–54PubMedCrossRefGoogle Scholar
  98. 98.
    Boyer JD, Wang B, Ugen KE, et al. In vivo protective anti-HIV immune responses in non-human primates through DNA immunization. J Med Primatol 1996 Jun; 25(3): 242–50PubMedCrossRefGoogle Scholar
  99. 99.
    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 Nov 22; 19(7–8): 764–78PubMedCrossRefGoogle Scholar
  100. 100.
    Wang R, Doolan DL, Le TP, et al. Induction of antigen-specific cytotoxic T lymphocytes in humans by a malaria DNA vaccine. Science 1998; 282(5388): 476–80PubMedCrossRefGoogle Scholar
  101. 101.
    Calarota S, Bratt G, Nordlund S, et al. Cellular cytotoxic response induced by DNA vaccination in HIV-1-infected patients. Lancet 1998 May 2; 351(9112): 1320–5PubMedCrossRefGoogle Scholar
  102. 102.
    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 Jul; 178(1): 92–100PubMedCrossRefGoogle Scholar
  103. 103.
    Ugen KE, Nyland SB, Boyer JD, et al. DNA vaccination with HIV-1 expressing constructs elicits immune responses in humans. Vaccine 1998; 16(19): 1818–21PubMedCrossRefGoogle Scholar
  104. 104.
    Richmond JF, Mustafa F, Lu S, et al. Screening of HIV-1 Env glycoproteins for the ability to raise neutralizing antibody using DNA immunization and recombinant vaccinia virus boosting. Virology 1997 Apr 14; 230(2): 265–74PubMedCrossRefGoogle Scholar
  105. 105.
    Mustafa F, Richmond JF, Fernandez-Larsson R, et al. HIV-1 Env glycoproteins from two series of primary isolates: replication phenotype and immunogenicity. Virology 1997 Mar 3; 229(1): 269–78PubMedCrossRefGoogle Scholar
  106. 106.
    Wang S, Chou TH, Sakhatskyy PV, et al. Identification of two neutralizing regions on the severe acute respiratory syndrome coronavirus spike glycoprotein produced from the mammalian expression system. J Virol 2005 Feb; 79(3): 1906–10PubMedCrossRefGoogle Scholar
  107. 107.
    Robinson HL, Montefiori DC, Johnson RP, et al. Neutralizing antibody-independent containment of immunodeficiency virus challenges by DNA priming and recombinant pox virus booster immunizations. Nat Med 1999; 5(5): 526–34PubMedCrossRefGoogle Scholar
  108. 108.
    Heller LC, Ugen K, Heller R. Electroporation for targeted gene transfer. Expert Opin Drug Deliv 2005 Mar; 2(2): 255–68PubMedCrossRefGoogle Scholar
  109. 109.
    Wang S, Zhang C, Zhang L, et al. The relative immunogenicity of DNA vaccines delivered by the intramuscular needle injection, electroporation and gene gun methods. Vaccine 2008 Apr 16; 26(17): 2100–10PubMedCrossRefGoogle Scholar
  110. 110.
    Aguiar JC, Hedstrom RC, Rogers WO, et al. Enhancement of the immune response in rabbits to a malaria DNA vaccine by immunization with a needle-free jet device. Vaccine 2001 Oct 12; 20(1–2): 275–80PubMedCrossRefGoogle Scholar
  111. 111.
    Haensler J, Verdelet C, Sanchez V, et al. Intradermal DNA immunization by using jet-injectors in mice and monkeys. Vaccine 1999 Feb 26; 17(7–8): 628–38PubMedCrossRefGoogle Scholar
  112. 112.
    Trimble C, Lin CT, Hung CF, et al. Comparison of the CD8+ T cell responses and antitumor effects generated by DNA vaccine administered through gene gun, biojector, and syringe. Vaccine 2003 Sep 8; 21(25–26): 4036–42PubMedCrossRefGoogle Scholar
  113. 113.
    Prausnitz MR. Microneedles for transdermal drug delivery. Adv Drug Deliv Rev 2004 Mar 27; 56(5): 581–7PubMedCrossRefGoogle Scholar
  114. 114.
    Deml L, Bojak A, Steck S, et al. Multiple effects of codon usage optimization on expression and immunogenicity of DNA candidate vaccines encoding the human immunodeficiency virus type 1 Gag protein. J Virol2001 Nov; 75(22): 10991–1001PubMedCrossRefGoogle Scholar
  115. 115.
    Wang S, Farfan-Arribas DJ, Shen S, et al. Relative contributions of codon usage, promoter efficiency and leader sequence to the antigen expression and immunogenicity of HIV-1 Env DNA vaccine. Vaccine 2006 May 22; 24(21): 4531–40PubMedCrossRefGoogle Scholar
  116. 116.
    zurMegede JZ, Chen MC, Doe B, et al. Increased expression and immunogenicity of sequence-modified human immunodeficiency virus type 1 gag gene. J Virol 2000; 74(6): 2628–35PubMedCrossRefGoogle Scholar
  117. 117.
    Lu S. Combination DNA plus protein HIV vaccines. Springer Semin Immunopathol 2006 Nov; 28(3): 255–65PubMedCrossRefGoogle Scholar
  118. 118.
    Richmond JF, Lu S, Santoro JC, et al. Studies of the neutralizing activity and avidity of anti-human immunodeficiency virus type 1 Env antibody elicited by DNA priming and protein boosting. J Virol 1998; 72(11): 9092–100PubMedGoogle Scholar
  119. 119.
    Barnett SW, Rajasekar S, Legg H, et al. Vaccination with HIV-1 gp120 DNA induces immune responses that are boosted by a recombinant gp120 protein subunit. Vaccine 1997 Jun; 15(8): 869–73PubMedCrossRefGoogle Scholar
  120. 120.
    Letvin NL, Montefiori DC, Yasutomi Y, et al. Potent, protective anti-HIV immune responses generated by bimodal HIV envelope DNA plus protein vaccination. Proc Natl Acad Sci U S A 1997 Aug 19; 94(17): 9378–83PubMedCrossRefGoogle Scholar
  121. 121.
    Wang S, Arthos J, Lawrence JM, et al. Enhanced immunogenicity of gp120 protein when combined with recombinant DNA priming to generate antibodies that neutralize the JR-FL primary isolate of human immunodeficiency virus type 1. J Virol 2005 Jun; 79(12): 7933–7PubMedCrossRefGoogle Scholar
  122. 122.
    Wang S, Pal R, Mascola JR, et al. Polyvalent HIV-1 Env vaccine formulations delivered by the DNA priming plus protein boosting approach are effective in generating neutralizing antibodies against primary human immunodeficiency virus type 1 isolates from subtypes A, B, C, D and E. Virology 2006 Jun 20; 350(1): 34–47PubMedCrossRefGoogle Scholar
  123. 123.
    Pal R, Wang S, Kalyanaraman VS, et al. Immunization of rhesus macaques with a polyvalent DNA prime/protein boost human immunodeficiency virus type 1 vaccine elicits protective antibody response against simian human immunodeficiency virus of R5 phenotype. Virology 2006 May 10; 348(2): 341–53PubMedCrossRefGoogle Scholar
  124. 124.
    Rasmussen RA, Hofmann-Lehman R, Montefiori DC, et al. DNA prime/protein boost vaccine strategy in neonatal macaques against simian human immunodeficiency virus. J Med Primatol 2002 Feb; 31(1): 40–60PubMedCrossRefGoogle Scholar
  125. 125.
    Goepfert PA, Tomaras GD, Horton H, et al. Durable HIV-1 antibody and T-cell responses elicited by an adjuvanted multi-protein recombinant vaccine in uninfected human volunteers. Vaccine 2007; 25: 510–8PubMedCrossRefGoogle Scholar
  126. 126.
    Kennedy JS, Co M, Green S, et al. The safety and tolerability of an HIV-1 DNA prime-protein boost vaccine (DP6-001) in healthy adult volunteers. Vaccine 2008 Aug 18; 26(35): 4420–4PubMedCrossRefGoogle Scholar
  127. 127.
    Vaine M, Wang S, Crooks ET, et al. Improved induction of antibodies against key neutralizing epitopes by human immunodeficiency virus type 1 gp120 DNA prime-protein boost vaccination compared to gp120 protein-only vaccination. J Virol 2008 Aug; 82(15): 7369–78PubMedCrossRefGoogle Scholar
  128. 128.
    Li Y, Migueles SA, Welcher B, et al. Broad HIV-1 neutralization mediated by CD4-binding site antibodies. Nat Med 2007 Sep; 13(9): 1032–4PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2009

Authors and Affiliations

  1. 1.Room 304, Laboratory of Nucleic Acid Vaccines, Department of MedicineUniversity of Massachusetts Medical SchoolWorcesterUSA

Personalised recommendations