1887

Abstract

Interleukin 1 (IL1) is an important regulator of inflammatory responses and contributes to host immune defence against infection. Vaccinia virus encodes a viral soluble IL1 receptor (IL1R), which modulates the acute-phase host response to infection and might influence the induction of immune responses against virus-associated antigens. Here, modified vaccinia virus Ankara (MVA) mutants defective in IL1R production were produced by insertion of selectable marker gene sequences that precisely deleted the IL1R coding sequences from the MVA genome (MVA-ΔIL1R). Analysis of MVA mutants indicated that deletion of the IL1R gene did not abrogate the formation of MVA progeny upon tissue culture propagation. After high-dose intranasal infection with MVA-ΔIL1R, mice showed no signs of fever or other illness, suggesting that the avirulent phenotype remained preserved for MVA-ΔIL1R. Following vaccination of mice, MVA-ΔIL1R or non-mutated MVA induced similar acute-phase immune responses. Importantly, when monitored at the memory phase, significantly higher vaccinia virus-specific total CD8 and HLA-A*0201-binding peptide epitope-specific T-cell responses were found after vaccination of HLA-A*0201-transgenic and non-transgenic mice with MVA-ΔIL1R. Moreover, 4–6 months after vaccination, MVA-ΔIL1R provided higher levels of protection against lethal respiratory challenge infection with virulent vaccinia virus strain Western Reserve compared with wild-type MVA. These data suggest that deletion of the viral IL1R gene may be considered a relevant approach to amplify the virus-specific CD8 memory T-cell response and duration of protective immunity obtained after MVA vaccination.

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2005-07-01
2024-03-28
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References

  1. Alcami A. 2003; Viral mimicry of cytokines, chemokines and their receptors. Nat Rev Immunol 3:36–50 [CrossRef]
    [Google Scholar]
  2. Alcami A., Smith G. 1992; A soluble receptor for interleukin-1 β encoded by vaccinia virus: a novel mechanism of virus modulation of the host response to infection. Cell 71:153–167 [CrossRef]
    [Google Scholar]
  3. Alcami A., Smith G. L. 1996; A mechanism for the inhibition of fever by a virus. Proc Natl Acad Sci U S A 93:11029–11034 [CrossRef]
    [Google Scholar]
  4. Amara R. R., Nigam P., Sharma S., Liu J., Bostik V. 2004; Long-lived poxvirus immunity, robust CD4 help, and better persistence of CD4 than CD8 T cells. J Virol 78:3811–3816 [CrossRef]
    [Google Scholar]
  5. Antoine G., Scheiflinger F., Dorner F., Falkner F. G. 1998; The complete genomic sequence of the modified vaccinia Ankara strain: comparison with other orthopoxviruses. Virology 244:365–396 [CrossRef]
    [Google Scholar]
  6. Belyakov I. M., Earl P., Dzutsev A. 8 other authors 2003; Shared modes of protection against poxvirus infection by attenuated and conventional smallpox vaccine viruses. Proc Natl Acad Sci U S A 100:9458–9463 [CrossRef]
    [Google Scholar]
  7. Blanchard T. J., Alcami A., Andrea P., Smith G. L. 1998; Modified vaccinia virus Ankara undergoes limited replication in human cells and lacks several immunomodulatory proteins: implications for use as a human vaccine. J Gen Virol 79:1159–1167
    [Google Scholar]
  8. Carroll M. W., Moss B. 1997; Host range and cytopathogenicity of the highly attenuated MVA strain of vaccinia virus: propagation and generation of recombinant viruses in a nonhuman mammalian cell line. Virology 238:198–211 [CrossRef]
    [Google Scholar]
  9. Corona Gutierrez C. M., Tinoco A., Lopez Contreras M., Navarro T., Calzado P., Vargas L., Reyes L., Posternak R., Rosales R. 2002; Clinical protocol. A phase II study: efficacy of the gene therapy of the MVA E2 recombinant virus in the treatment of precancerous lesions (NIC I and NIC II) associated with infection of oncogenic human papillomavirus. Hum Gene Ther 13:1127–1140 [CrossRef]
    [Google Scholar]
  10. Cosma A., Nagaraj R., Buhler S., Hinkula J., Busch D. H., Sutter G., Goebel F. D., Erfle V. 2003; Therapeutic vaccination with MVA-HIV-1 nef elicits nef-specific T-helper cell responses in chronically HIV-1 infected individuals. Vaccine 22:21–29 [CrossRef]
    [Google Scholar]
  11. Di Nicola M., Carlo-Stella C., Anichini A. 14 other authors 2003; Clinical protocol. Immunization of patients with malignant melanoma with autologous CD34+ cell-derived dendritic cells transduced ex vivo with a recombinant replication-deficient vaccinia vector encoding the human tyrosinase gene: a phase I trial. Hum Gene Ther 14:1347–1360 [CrossRef]
    [Google Scholar]
  12. Drexler I., Heller K., Wahren B., Erfle V., Sutter G. 1998; Highly attenuated modified vaccinia virus Ankara replicates in baby hamster kidney cells, a potential host for virus propagation, but not in various human transformed and primary cells. J Gen Virol 79:347–352
    [Google Scholar]
  13. Drexler I., Staib C., Kastenmuller W. 8 other authors 2003; Identification of vaccinia virus epitope-specific HLA-A*0201-restricted T cells and comparative analysis of smallpox vaccines. Proc Natl Acad Sci U S A 100:217–222 [CrossRef]
    [Google Scholar]
  14. Earl P. L., Americo J. L., Wyatt L. S. 15 other authors 2004; Immunogenicity of a highly attenuated MVA smallpox vaccine and protection against monkeypox. Nature 428:182–185 [CrossRef]
    [Google Scholar]
  15. Filippi C., Hugues S., Cazareth J., Julia V., Glaichenhaus N., Ugolini S. 2003; CD4+ T cell polarization in mice is modulated by strain-specific major histocompatibility complex-independent differences within dendritic cells. J Exp Med 198:201–209 [CrossRef]
    [Google Scholar]
  16. Guo Z., Zhang M., An H., Chen W., Liu S., Guo J., Yu Y., Cao X. 2003; Fas ligation induces IL-1 β -dependent maturation and IL-1 β -independent survival of dendritic cells: different roles of ERK and NF- κ B signaling pathways. Blood 102:4441–4447 [CrossRef]
    [Google Scholar]
  17. Hornemann S., Harlin O., Staib C., Kisling S., Erfle V., Kaspers B., Hacker G., Sutter G. 2003; Replication of modified vaccinia virus Ankara in primary chicken embryo fibroblasts requires expression of the interferon resistance gene E3L. J Virol 77:8394–8407 [CrossRef]
    [Google Scholar]
  18. Iwasaki A. 2003; The importance of CD11b+ dendritic cells in CD4+ T cell activation in vivo: with help from interleukin 1. J Exp Med 198:185–190 [CrossRef]
    [Google Scholar]
  19. Khayyamian S., Hutloff A., Buchner K., Grafe M., Henn V., Kroczek R. A., Mages H. W. 2002; ICOS-ligand, expressed on human endothelial cells, costimulates Th1 and Th2 cytokine secretion by memory CD4+ T cells. Proc Natl Acad Sci U S A 99:6198–6203 [CrossRef]
    [Google Scholar]
  20. Mayr A., Munz E. 1964; Veränderungen von Vaccinevirus durch Dauerpassagen in Hühnerfibroblastenkulturen. Zentralbl Bakteriol [Orig] 195:24
    [Google Scholar]
  21. Mayr A., Hochstein-Mintzel V., Stickl H. 1975; Abstammung, Eigenschaften und Verwendung des attenuierten Vaccinia-Stammes MVA. Infection 3:6–14 [CrossRef]
    [Google Scholar]
  22. Mayr A., Stickl H., Müller H., Danner K., Singer H. 1978; Der Pockenimpfstamm MVA: Marker, genetische Struktur, Erfahrungen mit der parenteralen Schutzimpfung und Verhalten im abwehrgeschwächten Organismus. Zentralbl Bakteriol [Orig B] 167375–390
    [Google Scholar]
  23. McConkey S. J., Reece W. 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]
  24. Meyer H., Sutter G., Mayr A. 1991; Mapping of deletions in the genome of the highly attenuated vaccinia virus MVA and their influence on virulence. J Gen Virol 72:1031–1038 [CrossRef]
    [Google Scholar]
  25. Moss B., Earl P. L. 1991; Preparation of cell cultures and vaccinia virus stocks. In Current Protocols in Molecular Biology pp. 16.16.11–16.16.17 Edited by Ausubel F. M., Brent R., Kingston R. E., Moore D. D., Seidman J. G., Smith J. A., Struhl K. New York: Wiley & Sons;
    [Google Scholar]
  26. Moss B., Shisler J. L. 2001; Immunology 101 at poxvirus U: immune evasion genes. Semin Immunol 13:59–66 [CrossRef]
    [Google Scholar]
  27. Moss B., Carroll M. W., Wyatt L. S. 12 other authors 1996; Host range restricted, non-replicating vaccinia virus vectors as vaccine candidates. Adv Exp Med Biol 397:7–13
    [Google Scholar]
  28. Pascolo S., Bervas N., Ure J. M., Smith A. G., Lemonnier F. A., Perarnau B. 1997; HLA-A2.1-restricted education and cytolytic activity of CD8+ T lymphocytes from β 2 microglobulin ( β 2m) HLA-A2.1 monochain transgenic H-2Db β 2m double knockout mice. J Exp Med 185:2043–2051 [CrossRef]
    [Google Scholar]
  29. Ramirez J. C., Gherardi M. M., Esteban M. 2000; Biology of attenuated modified vaccinia virus Ankara recombinant vector in mice: virus fate and activation of B- and T-cell immune responses in comparison with the Western Reserve strain and advantages as a vaccine. J Virol 74:923–933 [CrossRef]
    [Google Scholar]
  30. Reading P. C., Smith G. L. 2003a; Vaccinia virus interleukin-18-binding protein promotes virulence by reducing gamma interferon production and natural killer and T-cell activity. J Virol 77:9960–9968 [CrossRef]
    [Google Scholar]
  31. Reading P. C., Smith G. L. 2003b; A kinetic analysis of immune mediators in the lungs of mice infected with vaccinia virus and comparison with intradermal infection. J Gen Virol 84:1973–1983 [CrossRef]
    [Google Scholar]
  32. Reading P. C., Moore J. B., Smith G. L. 2003; Steroid hormone synthesis by vaccinia virus suppresses the inflammatory response to infection. J Exp Med 197:1269–1278 [CrossRef]
    [Google Scholar]
  33. Rochlitz C., Figlin R., Squiban P. 8 other authors 2003; Phase I immunotherapy with a modified vaccinia virus (MVA) expressing human MUC1 as antigen-specific immunotherapy in patients with MUC1-positive advanced cancer. J Gene Med 5:690–699 [CrossRef]
    [Google Scholar]
  34. Sambrook J., Fritsch E. F., Maniatis T. 1989 Molecular Cloning: a Laboratory Manual , 2nd edn. Cold Spring Harbor: NY: Cold Spring Harbor Laboratory;
    [Google Scholar]
  35. Santra S., Barouch D. H., Korioth-Schmitz B. 18 other authors 2004; Recombinant poxvirus boosting of DNA-primed rhesus monkeys augments peak but not memory T lymphocyte responses. Proc Natl Acad Sci U S A 101:11088–11093 [CrossRef]
    [Google Scholar]
  36. Sims J. E. 2002; IL-1 and IL-18 receptors, and their extended family. Curr Opin Immunol 14:117–122 [CrossRef]
    [Google Scholar]
  37. Spriggs M., Hruby D., Maliszewski C., Pickup D., Sims J., Buller R. M., VanSlyke J. 1992; Vaccinia and cowpox viruses encode a novel secreted interleukin-1-binding protein. Cell 71:145–152 [CrossRef]
    [Google Scholar]
  38. Staib C., Sutter G. 2003; Live viral vectors: vaccinia virus. Methods Mol Med 87:51–68
    [Google Scholar]
  39. Staib C., Drexler I., Ohlmann M., Wintersperger S., Erfle V., Sutter G. 2000; Transient host range selection for genetic engineering of modified vaccinia virus Ankara. Biotechniques 28: 1137–1142, 1144–1146, 1148
    [Google Scholar]
  40. Staib C., Lowel M., Erfle V., Sutter G. 2003; Improved host range selection for recombinant modified vaccinia virus Ankara. Biotechniques 34:694–696 698:700
    [Google Scholar]
  41. Stickl H., Hochstein-Mintzel V., Mayr A., Huber H., Schäfer H., Holzner A. 1974; MVA-Stufenimpfung gegen Pocken. Dtsch Med Wochenschr 99:2386–2392 [CrossRef]
    [Google Scholar]
  42. Stittelaar K. J., Kuiken T., de Swart R. L. 8 other authors; 2001; Safety of modified vaccinia virus Ankara (MVA) in immune-suppressed macaques. Vaccine 19:3700–3709 [CrossRef]
    [Google Scholar]
  43. Sutter G., Moss B. 1992; Nonreplicating vaccinia vector efficiently expresses recombinant genes. Proc Natl Acad Sci U S A 89:10847–10851 [CrossRef]
    [Google Scholar]
  44. Sutter G., Moss B. 1995; Novel vaccinia vector derived from the host range restricted and highly attenuated MVA strain of vaccinia virus. Dev Biol Stand 84:195–200
    [Google Scholar]
  45. Von Stebut E., Ehrchen J. M., Belkaid Y., Kostka S. L., Molle K., Knop J., Sunderkotter C., Udey M. C. 2003; Interleukin 1 α promotes Th1 differentiation and inhibits disease progression in Leishmania major -susceptible BALB/c mice. J Exp Med 198:191–199 [CrossRef]
    [Google Scholar]
  46. Williamson J. D., Reith R. W., Jeffrey L. J., Arrand J. R., Mackett M. 1990; Biological characterization of recombinant vaccinia viruses in mice infected by the respiratory route. J Gen Virol 71:2761–2767 [CrossRef]
    [Google Scholar]
  47. Wyatt L. S., Earl P. L., Eller L. A., Moss B. 2004; Highly attenuated smallpox vaccine protects mice with and without immune deficiencies against pathogenic vaccinia virus challenge. Proc Natl Acad Sci U S A 101:4590–4595 [CrossRef]
    [Google Scholar]
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