1887

Abstract

In this study, the design and preclinical development of a multigene human immunodeficiency virus type 1 (HIV-1) subtype C DNA vaccine are described, developed as part of the South African AIDS Vaccine Initiative (SAAVI). Genetic variation remains a major obstacle in the development of an HIV-1 vaccine and recent strategies have focused on constructing vaccines based on the subtypes dominant in the developing world, where the epidemic is most severe. The vaccine, SAAVI DNA-C, contains an equimolar mixture of two plasmids, pTHr.grttnC and pTHr.gp150CT, which express a polyprotein derived from Gag, reverse transcriptase (RT), Tat and Nef, and a truncated Env, respectively. Genes included in the vaccine were obtained from individuals within 3 months of infection and selection was based on closeness to a South African subtype C consensus sequence. All genes were codon-optimized for increased expression in humans. The genes have been modified for safety, stability and immunogenicity. Tat was inactivated through shuffling of gene fragments, whilst maintaining all potential epitopes; the active site of RT was mutated; 124 aa were removed from the cytoplasmic tail of gp160; and Nef and Gag myristylation sites were inactivated. Following vaccination of BALB/c mice, high levels of cytotoxic T lymphocytes were induced against multiple epitopes and the vaccine stimulated strong CD8 gamma interferon responses. In addition, high titres of antibodies to gp120 were induced in guinea pigs. This vaccine is the first component of a prime–boost regimen that is scheduled for clinical trials in humans in the USA and South Africa.

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2006-02-01
2019-11-14
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References

  1. Addo, M. M., Yu, X. G., Rathod, A. & 17 other authors ( 2003; ). Comprehensive epitope analysis of human immunodeficiency virus type 1 (HIV-1)-specific T-cell responses directed against the entire expressed HIV-1 genome demonstrate broadly directed responses, but no correlation to viral load. J Virol 77, 2081–2092.[CrossRef]
    [Google Scholar]
  2. Aiken, C., Konner, J., Landau, N. R., Lenburg, M. E. & Trono, D. ( 1994; ). Nef induces CD4 endocytosis: requirement for a critical dileucine motif in the membrane-proximal CD4 cytoplasmic domain. Cell 76, 853–864.[CrossRef]
    [Google Scholar]
  3. Allen, T. M., O'Connor, D. H., Jing, P. & 16 other authors ( 2000; ). Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia. Nature 407, 386–390.[CrossRef]
    [Google Scholar]
  4. Altfeld, M., Addo, M. M., Shankarappa, R. & 13 other authors ( 2003; ). Enhanced detection of human immunodeficiency virus type 1-specific T-cell responses to highly variable regions by using peptides based on autologous virus sequences. J Virol 77, 7330–7340.[CrossRef]
    [Google Scholar]
  5. Amara, R. R., Villinger, F., Altman, J. D. & 19 other authors ( 2001; ). Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA/MVA vaccine. Science 292, 69–74.[CrossRef]
    [Google Scholar]
  6. Amara, R. R., Smith, J. M., Staprans, S. I. & 13 other authors ( 2002; ). Critical role for Env as well as Gag-Pol in control of a simian-human immunodeficiency virus 89.6P challenge by a DNA prime/recombinant modified vaccinia virus Ankara vaccine. J Virol 76, 6138–6146.[CrossRef]
    [Google Scholar]
  7. Barouch, D. H. & Letvin, N. L. ( 2004; ). HIV escape from cytotoxic T lymphocytes: a potential hurdle for vaccines? Lancet 364, 10–11.
    [Google Scholar]
  8. Barouch, D. H., Santra, S., Schmitz, J. E. & 26 other authors ( 2000; ). Control of viremia and prevention of clinical AIDS in rhesus monkeys by cytokine-augmented DNA vaccination. Science 290, 486–492.[CrossRef]
    [Google Scholar]
  9. Barouch, D. H., Kunstman, J., Kuroda, M. J. & 11 other authors ( 2002; ). Eventual AIDS vaccine failure in a rhesus monkey by viral escape from cytotoxic T lymphocytes. Nature 415, 335–339.[CrossRef]
    [Google Scholar]
  10. Barouch, D. H., Yang, Z.-Y., Kong, W.-P. & 9 other authors ( 2005; ). A human T-cell leukemia virus type 1 regulatory element enhances the immunogenicity of human immunodeficiency virus type 1 DNA vaccines in mice and nonhuman primates. J Virol 79, 8828–8834.[CrossRef]
    [Google Scholar]
  11. Betti, M., Voltan, R., Marchisio, M., Mantovani, I., Boarini, C., Nappi, F., Ensoli, B. & Caputo, A. ( 2001; ). Characterization of HIV-1 Tat proteins mutated in the transactivation domain for prophylactic and therapeutic application. Vaccine 19, 3408–3419.[CrossRef]
    [Google Scholar]
  12. Betts, M. R., Ambrozak, D. R., Douek, D. C., Bonhoeffer, S., Brenchley, J. M., Casazza, J. P., Koup, R. A. & Picker, L. J. ( 2001; ). Analysis of total human immunodeficiency virus (HIV)-specific CD4+ and CD8+ T-cell responses: relationship to viral load in untreated HIV infection. J Virol 75, 11983–11991.[CrossRef]
    [Google Scholar]
  13. Boykins, R. A., Mahieux, R., Shankavaram, U. T. & 8 other authors ( 1999; ). Cutting edge: a short polypeptide domain of HIV-1-Tat protein mediates pathogenesis. J Immunol 163, 15–20.
    [Google Scholar]
  14. Buseyne, F., Le Chenadec, J., Corre, B., Porrot, F., Burgard, M., Rouzioux, C., Blanche, S., Mayaux, M.-J. & Rivière, Y. ( 2002; ). Inverse correlation between memory Gag-specific cytotoxic T lymphocytes and viral replication in human immunodeficiency virus-infected children. J Infect Dis 186, 1589–1596.[CrossRef]
    [Google Scholar]
  15. Casimiro, D. R., Tang, A. M., Perry, H. C. & 15 other authors ( 2002; ). Vaccine-induced immune responses in rodents and nonhuman primates by use of a humanized human immunodeficiency virus type 1 pol gene. J Virol 76, 185–194.[CrossRef]
    [Google Scholar]
  16. Chao, S.-F., Chan, V. L., Juranka, P., Kaplan, A. H., Swanstrom, R. & Hutchison, C. A., III ( 1995; ). Mutational sensitivity patterns define critical residues in the palm subdomain of the reverse transcriptase of human immunodeficiency virus type 1. Nucleic Acids Res 23, 803–810.[CrossRef]
    [Google Scholar]
  17. Connick, E., Schlichtemeier, R. L., Purner, M. B. & 8 other authors ( 2001; ). Relationship between human immunodeficiency virus type 1 (HIV-1)-specific memory cytotoxic T lymphocytes and virus load after recent HIV-1 seroconversion. J Infect Dis 184, 1465–1469.[CrossRef]
    [Google Scholar]
  18. Coplan, P. M., Gupta, S. B., Dubey, S. A. & 23 other authors ( 2005; ). Cross-reactivity of anti-HIV-1 T cell immune responses among the major HIV-1 clades in HIV-1-positive individuals from 4 continents. J Infect Dis 191, 1427–1434.[CrossRef]
    [Google Scholar]
  19. Cranenburgh, R. M., Hanak, J. A. J., Williams, S. G. & Sherratt, D. J. ( 2001; ). Escherichia coli strains that allow antibiotic-free plasmid selection and maintenance by repressor titration. Nucleic Acids Res 29, e26.[CrossRef]
    [Google Scholar]
  20. Department of Health South Africa ( 2005; ). National HIV and Syphilis Antenatal Sero-prevalence Survey in South Africa 2004. http://www.doh.gov.za/docs/reports/2004/hiv-syphilis.pdf
  21. Edwards, T. G., Wyss, S., Reeves, J. D., Zolla-Pazner, S., Hoxie, J. A., Doms, R. W. & Baribaud, F. ( 2002; ). Truncation of the cytoplasmic domain induces exposure of conserved regions in the ectodomain of human immunodeficiency virus type 1 envelope protein. J Virol 76, 2683–2691.[CrossRef]
    [Google Scholar]
  22. Ferrari, G., Humphrey, W., McElrath, M. J., Excler, J. L., Duliege, A. M., Clements, M. L., Corey, L. C., Bolognesi, D. P. & Weinhold, K. J. ( 1997; ). Clade B-based HIV-1 vaccines elicit cross-clade cytotoxic T lymphocyte reactivities in uninfected volunteers. Proc Natl Acad Sci U S A 94, 1396–1401.[CrossRef]
    [Google Scholar]
  23. Gao, F., Weaver, E. A., Lu, Z. J. & 13 other authors ( 2005; ). Antigenicity and immunogenicity of a synthetic human immunodeficiency virus type 1 group M consensus envelope glycoprotein. J Virol 79, 1154–1163.[CrossRef]
    [Google Scholar]
  24. Gaschen, B., Taylor, J., Yusim, K. & 8 other authors ( 2002; ). AIDS diversity considerations in HIV-1 vaccine selection. Science 296, 2354–2360.[CrossRef]
    [Google Scholar]
  25. Guevara, H., Johnston, E., Zijenah, L., Tobaiwa, O., Mason, P., Contag, C., Mahomed, K., Hendry, M. & Katzenstein, D. ( 2000; ). Prenatal transmission of subtype C HIV-1 in Zimbabwe: HIV-1 RNA and DNA in maternal and cord blood. J Acquir Immune Defic Syndr 25, 390–397.[CrossRef]
    [Google Scholar]
  26. Hanke, T. & McMichael, A. J. ( 2000; ). Design and construction of an experimental HIV-1 vaccine for a year-2000 clinical trial in Kenya. Nat Med 6, 951–955.[CrossRef]
    [Google Scholar]
  27. Hanke, T., Schneider, J., Gilbert, S. C., Hill, A. V. S. & McMichael, A. ( 1998; ). DNA multi-CTL epitope vaccines for HIV and Plasmodium falciparum: immunogenicity in mice. Vaccine 16, 426–435.[CrossRef]
    [Google Scholar]
  28. Hanke, T., Neumann, V. C., Blanchard, T. J., Sweeney, P., Hill, A. V. S., Smith, G. L. & McMichael, A. ( 1999; ). Effective induction of HIV-specific CTL by multi-epitope using gene gun in a combined vaccination regime. Vaccine 17, 589–596.[CrossRef]
    [Google Scholar]
  29. Hasson, T., Gillespie, P. G., Garcia, J. A., MacDonald, R. B., Zhao, Y., Yee, A. G., Mooseker, M. S. & Corey, D. P. ( 1997; ). Unconventional myosins in inner-ear sensory epithelia. J Cell Biol 137, 1287–1307.[CrossRef]
    [Google Scholar]
  30. Hussein, M., Abebe, A., Pollakis, G., Brouwer, M., Petros, B., Fontanet, A. L. & Rinke de Wit, T. F. ( 2000; ). HIV-1 subtype C in commercial sex workers in Addis Ababa, Ethiopia. J Acquir Immune Defic Syndr 23, 120–127.[CrossRef]
    [Google Scholar]
  31. HVTN ( 2005; ). The Pipeline Project: Vaccines in Development. http://chi.ucsf.edu/vaccines/
  32. IAVI ( 2005; ). IAVI Report: Ongoing Trials of Preventative HIV Vaccines. http://www.iavireport.org/specials/OngoingTrialsofPreventiveHIVVaccines.asp
  33. Kaufmann, D. E., Bailey, P. M., Sidney, J. & 12 other authors ( 2004; ). Comprehensive analysis of human immunodeficiency virus type 1-specific CD4 responses reveals marked immunodominance of gag and nef and the presence of broadly recognized peptides. J Virol 78, 4463–4477.[CrossRef]
    [Google Scholar]
  34. Kjerrström, A., Hinkula, J., Engström, G., Ovod, V., Krohn, K., Benthin, R. & Wahren, B. ( 2001; ). Interactions of single and combined human immunodeficiency virus type 1 (HIV-1) DNA vaccines. Virology 284, 46–61.[CrossRef]
    [Google Scholar]
  35. Kong, W.-P., Huang, Y., Yang, Z.-Y., Chakrabarti, B. K., Moodie, Z. & Nabel, G. J. ( 2003; ). Immunogenicity of multiple gene and clade human immunodeficiency virus type 1 DNA vaccines. J Virol 77, 12764–12772.[CrossRef]
    [Google Scholar]
  36. Korber, B., Gaschen, B., Yusim, K., Thakallapally, R., Kesmir, C. & Detours, V. ( 2001; ). Evolutionary and immunological implications of contemporary HIV-1 variation. Br Med Bull 58, 19–42.[CrossRef]
    [Google Scholar]
  37. Letvin, N. L., Huang, Y., Chakrabarti, B. K. & 15 other authors ( 2004; ). Heterologous envelope immunogens contribute to AIDS vaccine protection in rhesus monkeys. J Virol 78, 7490–7497.[CrossRef]
    [Google Scholar]
  38. Lichterfeld, M., Yu, X. G., Cohen, D. & 11 other authors ( 2004; ). HIV-1 Nef is preferentially recognized by CD8 T cells in primary HIV-1 infection despite a relatively high degree of genetic diversity. AIDS 18, 1383–1392.[CrossRef]
    [Google Scholar]
  39. Lole, K. S., Bollinger, R. C., Paranjape, R. S., Gadkari, D., Kulkarni, S. S., Novak, N. G., Ingersoll, R., Sheppard, H. W. & Ray, S. C. ( 1999; ). Full-length human immunodeficiency virus type 1 genomes from subtype C-infected seroconverters in India, with evidence of intersubtype recombination. J Virol 73, 152–160.
    [Google Scholar]
  40. Lynch, J. A., deSouza, M., Robb, M. D., Markowitz, L., Nitayaphan, S., Sapan, C. V., Mann, D. L., Birx, D. L. & Cox, J. H. ( 1998; ). Cross-clade cytotoxic T cell response to human immunodeficiency virus type 1 proteins among HLA disparate North Americans and Thais. J Infect Dis 178, 1040–1046.[CrossRef]
    [Google Scholar]
  41. Masemola, A., Mashishi, T., Khoury, G. & 15 other authors ( 2004; ). Hierarchical targeting of subtype C human immunodeficiency virus type 1 proteins by CD8+ T cells: correlation with viral load. J Virol 78, 3233–3243.[CrossRef]
    [Google Scholar]
  42. McConkey, S. J., Reece, W. H. H., Moorthy, V. S. & 25 other authors ( 2003; ). Enhanced T-cell immunogenicity of plasmid DNA vaccines boosted by recombinant modified vaccinia virus Ankara in humans. Nat Med 9, 729–735.[CrossRef]
    [Google Scholar]
  43. Moorthy, V. S., Pinder, M., Reece, W. H. H. & 8 other authors ( 2003; ). Safety and immunogenicity of DNA/modified vaccinia virus Ankara malaria vaccination in African adults. J Infect Dis 188, 1239–1244.[CrossRef]
    [Google Scholar]
  44. Moorthy, V. S., Imoukhuede, E. B., Keating, S., Pinder, M., Webster, D., Skinner, M. A., Gilbert, S. C., Walraven, G. & Hill, A. V. S. ( 2004; ). Phase 1 evaluation of 3 highly immunogenic prime-boost regimens, including a 12-month reboosting vaccination, for malaria vaccination in Gambian men. J Infect Dis 189, 2213–2219.[CrossRef]
    [Google Scholar]
  45. Muthumani, K., Kudchodkar, S., Zhang, D., Bagarazzi, M. L., Kim, J. J., Boyer, J. D., Ayyavoo, V., Pavlakis, G. N. & Weiner, D. B. ( 2002; ). Issues for improving multiplasmid DNA vaccines for HIV-1. Vaccine 20, 1999–2003.[CrossRef]
    [Google Scholar]
  46. Mwau, M., Cebere, I., Sutton, J. & 16 other authors ( 2004; ). A human immunodeficiency virus 1 (HIV-1) clade A vaccine in clinical trials: stimulation of HIV-specific T-cell responses by DNA and recombinant modified vaccinia virus Ankara (MVA) vaccines in humans. J Gen Virol 85, 911–919.[CrossRef]
    [Google Scholar]
  47. Nkolola, J. P., Wee, E. G.-T., Im, E.-J., Jewell, C. P., Chen, N., Xu, X.-N., McMichael, A. J. & Hanke, T. ( 2004; ). Engineering RENTA, a DNA prime-MVA boost HIV vaccine tailored for Eastern and Central Africa. Gene Ther 11, 1068–1080.[CrossRef]
    [Google Scholar]
  48. Novitsky, V., Rybak, N., McLane, M. F. & 13 other authors ( 2001; ). Identification of human immunodeficiency virus type 1 subtype C Gag-, Tat-, Rev-, and Nef-specific elispot-based cytotoxic T-lymphocyte responses for AIDS vaccine design. J Virol 75, 9210–9228.[CrossRef]
    [Google Scholar]
  49. Novitsky, V., Cao, H., Rybak, N. & 9 other authors ( 2002; ). Magnitude and frequency of cytotoxic T-lymphocyte responses: identification of immunodominant regions of human immunodeficiency virus type 1 subtype C. J Virol 76, 10155–10168.[CrossRef]
    [Google Scholar]
  50. Osmanov, S., Pattou, C., Walker, N., Schwardlander, B. & Esparza, J. ( 2002; ). Estimated global distribution and regional spread of HIV-1 genetic subtypes in the year 2000. J Acquir Immune Defic Syndr 29, 184–190.[CrossRef]
    [Google Scholar]
  51. Park, J., Ryu, J., Kim, K.-A. & 7 other authors ( 2002; ). Mutational analysis of a human immunodeficiency virus type 1 Tat protein transduction domain which is required for delivery of an exogenous protein into mammalian cells. J Gen Virol 83, 1173–1181.
    [Google Scholar]
  52. Ramalingam, S., Kannangai, R., Vijayakumar, T. S., Mathai, D., Abraham, O. C., Subramanian, S., Purpali, P., Jesudason, M. V. & Sridharan, G. ( 2005; ). Subtype and cytokine profiles of HIV infected individuals from south India. Indian J Med Res 121, 226–234.
    [Google Scholar]
  53. Robinson, H. L., Montefiori, D. C., Johnson, R. P. & 14 other authors ( 1999; ). Neutralizing antibody-independent containment of immunodeficiency virus challenges by DNA priming and recombinant pox virus booster immunizations. Nat Med 5, 526–534.[CrossRef]
    [Google Scholar]
  54. Sadagopal, S., Amara, R. R., Montefiori, D. C., Wyatt, L. S., Staprans, S. I., Kozyr, N. L., McClure, H. M., Moss, B. & Robinson, H. L. ( 2005; ). Signature for long-term vaccine-mediated control of a simian and human immunodeficiency virus 89.6P challenge: stable low-breadth and low-frequency T-cell response capable of coproducing gamma interferon and interleukin-2. J Virol 79, 3243–3253.[CrossRef]
    [Google Scholar]
  55. Schwartz, O., Maréchal, V., Le Gall, S., Lemonnier, F. & Heard, J.-M. ( 1996; ). Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein. Nat Med 2, 338–342.[CrossRef]
    [Google Scholar]
  56. Seaman, M. S., Xu, L., Beaudry, K. & 11 other authors ( 2005; ). Multiclade human immunodeficiency virus type 1 envelope immunogens elicit broad cellular and humoral immunity in rhesus monkeys. J Virol 79, 2956–2963.[CrossRef]
    [Google Scholar]
  57. Shiver, J. W., Fu, T.-M., Chen, L. & 49 other authors ( 2002; ). Replication-incompetent adenoviral vaccine vector elicits effective anti-immunodeficiency-virus immunity. Nature 415, 331–335.[CrossRef]
    [Google Scholar]
  58. Smith, J. M., Amara, R. R., McClure, H. M. & 13 other authors ( 2004; ). Multiprotein HIV type 1 clade B DNA/MVA vaccine: construction, safety, and immunogenicity in macaques. AIDS Res Hum Retroviruses 20, 654–665.[CrossRef]
    [Google Scholar]
  59. Travers, S. A. A., Clewley, J. P., Glynn, J. R., Fine, P. E. M., Crampin, A. C., Sibande, F., Mulawa, D., McInerney, J. O. & McCormack, G. P. ( 2004; ). Timing and reconstruction of the most recent common ancestor of the subtype C clade of human immunodeficiency virus type 1. J Virol 78, 10501–10506.[CrossRef]
    [Google Scholar]
  60. UNAIDS ( 2004; ). Report on the Global HIV/AIDS Epidemic: 4th Global Report. http://www.unaids.org
  61. van Harmelen, J. H., van der Ryst, E., Loubser, A. S., York, D., Madurai, S., Lyons, S., Wood, R. & Williamson, C. ( 1999; ). A predominantly HIV type 1 subtype C-restricted epidemic in South African urban populations. AIDS Res Hum Retroviruses 15, 395–398.[CrossRef]
    [Google Scholar]
  62. van Harmelen, J. H., Shephard, E., Thomas, R., Hanke, T., Williamson, A.-L. & Williamson, C. ( 2003; ). Construction and characterisation of a candidate HIV-1 subtype C DNA vaccine for South Africa. Vaccine 21, 4380–4389.[CrossRef]
    [Google Scholar]
  63. Vuola, J. M., Keating, S., Webster, D. P., Berthoud, T., Dunachie, S., Gilbert, S. C. & Hill, A. V. S. ( 2005; ). Differential immunogenicity of various heterologous prime-boost vaccine regimens using DNA and viral vectors in healthy volunteers. J Immunol 174, 449–455.[CrossRef]
    [Google Scholar]
  64. Vzorov, A. N., Lea-Fox, D. & Compans, R. W. ( 1999; ). Immunogenicity of full length and truncated SIV envelope proteins. Viral Immunol 12, 205–215.[CrossRef]
    [Google Scholar]
  65. Wild, J., Bojak, A., Deml, L. & Wagner, R. ( 2004; ). Influence of polypeptide size and intracellular sorting on the induction of epitope-specific CTL responses by DNA vaccines in a mouse model. Vaccine 22, 1732–1743.[CrossRef]
    [Google Scholar]
  66. Williams, S. G., Cranenburgh, R. M., Weiss, A. M. E., Wrighton, C. J., Sherratt, D. J. & Hanak, J. A. J. ( 1998; ). Repressor titration: a novel system for selection and stable maintenance of recombinant plasmids. Nucleic Acids Res 26, 2120–2124.[CrossRef]
    [Google Scholar]
  67. Williamson, C., Morris, L., Maughan, M. F. & 12 other authors ( 2003; ). Characterization and selection of HIV-1 subtype C isolates for use in vaccine development. AIDS Res Hum Retroviruses 19, 133–144.[CrossRef]
    [Google Scholar]
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