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Abstract

Chorioallantois vaccinia virus Ankara (CVA) is the parental virus of modified vaccinia virus Ankara (MVA), which was derived from CVA by more than 570 passages in chicken embryo fibroblasts (CEF). MVA became severely host-cell-restricted to avian cells and has strongly diminished virulence in mammalian hosts, while maintaining good immunogenicity. We determined the complete coding sequence of the parental CVA and mapped the exact positions of the six major deletions that emerged in the MVA genome. All six major deletions occurred in regions of the CVA genome where one or more truncated or fragmented open reading frames (ORFs) pre-existed. The CVA genome contains 229 ORFs of which 51 are fragments of full-length orthopoxvirus (OPV) genes, including fragmented orthologues of C9L and M1L (encoding two well-conserved ankyrin-like proteins), A39R (encoding a semaphorin-like protein) and A55R (encoding a kelch-like protein). Phylogenetic analysis demonstrated that MVA was most closely related to CVA, followed by the vaccinia virus (VACV) strain DUKE, a patient-derived isolate of the Dryvax vaccine virus. Loss or mutation of genes outside the six major deletions are assumed to contribute to the restricted host range phenotype of MVA. In support of this notion, deletions, insertions and non-synonymous mutations were found in 122 of the 195 ORFs remaining in MVA when compared with their CVA counterparts. Thus, detailed knowledge of the CVA genomic sequence is a prerequisite to further dissect the genetic basis of the MVA host range phenotype as well as the particular immunological properties of MVA.

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2007-12-01
2024-12-08
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References

  1. Alcami A., Symons J. A., Collins P. D., Williams T. J., Smith G. L. 1998; Blockade of chemokine activity by a soluble chemokine binding protein from vaccinia virus. J Immunol 160:624–633
    [Google Scholar]
  2. Alcami A., Khanna A., Paul N. L., Smith G. L. 1999; Vaccinia virus strains Lister, USSR and Evans express soluble and cell-surface tumour necrosis factor receptors. J Gen Virol 80:949–959
    [Google Scholar]
  3. Ali A. N., Turner P. C., Brooks M. A., Moyer R. W. 1994; The SPI-1 gene of rabbitpox virus determines host range and is required for hemorrhagic pock formation. Virology 202:305–314 [CrossRef]
    [Google Scholar]
  4. Altschul S. F., Madden T. L., Schaffer A. A., Zhang J., Zhang Z., Miller W., Lipman D. J. 1997; Gapped blast and psi-blast: a new generation of protein database search programs. Nucleic Acids Res 25:3389–3402 [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. Badger J. H., Olsen G. J. 1999; critica: coding region identification tool invoking comparative analysis. Mol Biol Evol 16:512–524 [CrossRef]
    [Google Scholar]
  7. Beard P. M., Froggatt G. C., Smith G. L. 2006; Vaccinia virus kelch protein A55 is a 64 kDa intracellular factor that affects virus-induced cytopathic effect and the outcome of infection in a murine intradermal model. J Gen Virol 87:1521–1529 [CrossRef]
    [Google Scholar]
  8. Beattie E., Kauffman E. B., Martinez H., Perkus M. E., Jacobs B. L., Paoletti E., Tartaglia J. 1996; Host-range restriction of vaccinia virus E3L-specific deletion mutants. Virus Genes 12:89–94 [CrossRef]
    [Google Scholar]
  9. 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]
  10. Castresana J. 2000; Selection of conserved blocks from multiple alignments for their use in phylogenetic analysis. Mol Biol Evol 17:540–552 [CrossRef]
    [Google Scholar]
  11. Chang H. W., Uribe L. H., Jacobs B. L. 1995; Rescue of vaccinia virus lacking the E3L gene by mutants of E3L. J Virol 69:6605–6608
    [Google Scholar]
  12. Cooray S., Bahar M. W., Abrescia N. G., McVey C. E., Bartlett N. W., Chen R. A., Stuart D. I., Grimes J. M., Smith G. L. 2007; Functional and structural studies of the vaccinia virus virulence factor N1 reveal a Bcl-2-like anti-apoptotic protein. J Gen Virol 88:1656–1666 [CrossRef]
    [Google Scholar]
  13. Da Silva M., Upton C. 2005; Using purine skews to predict genes in AT-rich poxviruses. BMC Genomics 6:22 [CrossRef]
    [Google Scholar]
  14. Delcher A. L., Harmon D., Kasif S., White O., Salzberg S. L. 1999; Improved microbial gene identification with glimmer. Nucleic Acids Res 27:4636–4641 [CrossRef]
    [Google Scholar]
  15. DiPerna G., Stack J., Bowie A. G., Boyd A., Kotwal G., Zhang Z., Arvikar S., Latz E., Fitzgerald K. A., Marshall W. L. 2004; Poxvirus protein N1L targets the I- κ B kinase complex, inhibits signaling to NF- κ B by the tumor necrosis factor superfamily of receptors, and inhibits NF- κ B and IRF3 signaling by toll-like receptors. J Biol Chem 279:36570–36578 [CrossRef]
    [Google Scholar]
  16. 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]
  17. Felsenstein J. 1997; An alternating least squares approach to inferring phylogenies from pairwise distances. Syst Biol 46:101–111 [CrossRef]
    [Google Scholar]
  18. Fenner F., Henderson D. A., Arita I., Jezek Z., Ladnyi I. D. 1988 History of International Public Health: Smallpox and Its Eradication Geneva: World Health Organization;
    [Google Scholar]
  19. Finn R. D., Mistry J., Schuster-Bockler B., Griffiths-Jones S., Hollich V., Lassmann T., Moxon S., Marshall M., Khanna A. other authors 2006; Pfam: clans, web tools and services. Nucleic Acids Res 34:D247–D251 [CrossRef]
    [Google Scholar]
  20. Gillard S., Spehner D., Drillien R. 1985; Mapping of a vaccinia host range sequence by insertion into the viral thymidine kinase gene. J Virol 53:316–318
    [Google Scholar]
  21. Goebel S. J., Johnson G. P., Perkus M. E., Davis S. W., Winslow J. P., Paoletti E. 1990; The complete DNA sequence of vaccinia virus. Virology 179:247–263 [CrossRef]
    [Google Scholar]
  22. Gubser C., Hue S., Kellam P., Smith G. L. 2004; Poxvirus genomes: a phylogenetic analysis. J Gen Virol 85:105–117 [CrossRef]
    [Google Scholar]
  23. Harrer E., Bauerle M., Ferstl B., Chaplin P., Petzold B., Mateo L., Handley A., Tzatzaris M., Vollmar J. other authors 2005; Therapeutic vaccination of HIV-1-infected patients on HAART with a recombinant HIV-1 nef-expressing MVA: safety, immunogenicity and influence on viral load during treatment interruption. Antivir Ther 10:285–300
    [Google Scholar]
  24. Herrlich A., Mayr A. 1954; Comparative experimental works on cow pox virus vaccines. Arch Hyg Bakteriol 138:479–504 (in German
    [Google Scholar]
  25. Herrlich A., Mayr A. 1955; Differentiation of animal poxviruses in the embryonated chicken egg. Arch Hyg Bakteriol 139:444 (in German
    [Google Scholar]
  26. Herrlich A., Mayr A. 1957; Smallpox vaccine from tissue culture from a bull's tongue; at the same time a contribution to the question of culture vaccines. Arch Gesamte Virusforsch 7:284–296 (in German [CrossRef]
    [Google Scholar]
  27. Hsiao J. C., Chao C. C., Young M. J., Chang Y. T., Cho E. C., Chang W. 2006; A poxvirus host range protein, CP77, binds to a cellular protein, HMG20A, and regulates its dissociation from the vaccinia virus genome in CHO-K1 cells. J Virol 80:7714–7728 [CrossRef]
    [Google Scholar]
  28. Kettle S., Blake N. W., Law K. M., Smith G. L. 1995; Vaccinia virus serpins B13R (SPI-2) and B22R (SPI-1) encode M(r) 38.5 and 40K, intracellular polypeptides that do not affect virus virulence in a murine intranasal model. Virology 206:136–147 [CrossRef]
    [Google Scholar]
  29. Krause L., McHardy A. C., Nattkemper T. W., Pühler A., Stoye J., Meyer F. 2007; gismo–gene identification using a support vector machine for ORF classification. Nucleic Acids Res 35:540–549
    [Google Scholar]
  30. Li G., Chen N., Feng Z., Buller R. M., Osborne J., Harms T., Damon I., Upton C., Esteban D. J. 2006; Genomic sequence and analysis of a vaccinia virus isolate from a patient with a smallpox vaccine-related complication. Virol J 3:88 [CrossRef]
    [Google Scholar]
  31. Linke B., McHardy A. C., Neuweger H., Krause L., Meyer F. 2006; reganor: a gene prediction server for prokaryotic genomes and a database of high quality gene predictions for prokaryotes. Appl Bioinformatics 5:193–198 [CrossRef]
    [Google Scholar]
  32. Mackett M., Archard L. C. 1979; Conservation and variation in Orthopoxvirus genome structure. J Gen Virol 45:683–701 [CrossRef]
    [Google Scholar]
  33. Mayr A., Danner K. 1978; Vaccination against pox diseases under immunosuppressive conditions. Dev Biol Stand 41:225–234
    [Google Scholar]
  34. Mayr A., Munz E. 1964; Changes in the vaccinia virus through continuing passages in chick embryo fibroblast cultures. Zentralbl Bakteriol 195:24–35 (in German
    [Google Scholar]
  35. Mayr A., Hochstein-Mintzel V., Stickl H. 1975; Passage history, properties, and use of the attenuated vaccinia virus strain Ankara. Infection 3:6–14 (in German [CrossRef]
    [Google Scholar]
  36. McKelvey T. A., Andrews S. C., Miller S. E., Ray C. A., Pickup D. J. 2002; Identification of the orthopoxvirus p4c gene, which encodes a structural protein that directs intracellular mature virus particles into A-type inclusions. J Virol 76:11216–11225 [CrossRef]
    [Google Scholar]
  37. 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]
  38. Meyer F., Goesmann A., McHardy A. C., Bartels D., Bekel T., Clausen J., Kalinowski J., Linke B., Rupp O. other authors 2003; GenDB–an open source genome annotation system for prokaryote genomes. Nucleic Acids Res 31:2187–2195 [CrossRef]
    [Google Scholar]
  39. Monath T. P., Caldwell J. R., Mundt W., Fusco J., Johnson C. S., Buller M., Liu J., Gardner B., Downing G. other authors 2004; ACAM2000 clonal Vero cell culture vaccinia virus (New York City Board of Health strain)–a second-generation smallpox vaccine for biological defense. Int J Infect Dis 8 (Suppl. 2):S31–S44 [CrossRef]
    [Google Scholar]
  40. Morikawa S., Sakiyama T., Hasegawa H., Saijo M., Maeda A., Kurane I., Maeno G., Kimura J., Hirama C. other authors 2005; An attenuated LC16m8 smallpox vaccine: analysis of full-genome sequence and induction of immune protection. J Virol 79:11873–11891 [CrossRef]
    [Google Scholar]
  41. Mossman K., Lee S. F., Barry M., Boshkov L., McFadden G. 1996; Disruption of M-T5, a novel myxoma virus gene member of poxvirus host range superfamily, results in dramatic attenuation of myxomatosis in infected European rabbits. J Virol 70:4394–4410
    [Google Scholar]
  42. Oguiura N., Spehner D., Drillien R. 1993; Detection of a protein encoded by the vaccinia virus C7L open reading frame and study of its effect on virus multiplication in different cell lines. J Gen Virol 74:1409–1413 [CrossRef]
    [Google Scholar]
  43. Parker R. F., Bronson L. H., Green R. H. 1941; Further studies on the infectious unit of vaccinia. J Exp Med 74:263–281 [CrossRef]
    [Google Scholar]
  44. Perkus M. E., Goebel S. J., Davis S. W., Johnson G. P., Limbach K., Norton E. K., Paoletti E. 1990; Vaccinia virus host range genes. Virology 179:276–286 [CrossRef]
    [Google Scholar]
  45. Pires de Miranda M., Reading P. C., Tscharke D. C., Murphy B. J., Smith G. L. 2003; The vaccinia virus kelch-like protein C2L affects calcium-independent adhesion to the extracellular matrix and inflammation in a murine intradermal model. J Gen Virol 84:2459–2471 [CrossRef]
    [Google Scholar]
  46. Shchelkunov S. N., Safronov P. F., Totmenin A. V., Petrov N. A., Ryazankina O. I., Gutorov V. V., Kotwal G. J. 1998; The genomic sequence analysis of the left and right species-specific terminal region of a cowpox virus strain reveals unique sequences and a cluster of intact ORFs for immunomodulatory and host range proteins. Virology 243:432–460 [CrossRef]
    [Google Scholar]
  47. Staib C., Sutter G. 2003; Live viral vectors: vaccinia virus. Methods Mol Med 87:51–68
    [Google Scholar]
  48. Stickl H., Hochstein-Mintzel V., Mayr A., Huber H. C., Schafer H., Holzner A. 1974; MVA vaccination against smallpox: clinical tests with an attenuated live vaccinia virus strain (MVA). Dtsch Med Wochenschr 99:2386–2392 (in German [CrossRef]
    [Google Scholar]
  49. Sutter G., Ramsey-Ewing A., Rosales R., Moss B. 1994; Stable expression of the vaccinia virus K1L gene in rabbit cells complements the host range defect of a vaccinia virus mutant. J Virol 68:4109–4116
    [Google Scholar]
  50. Thompson J. D., Higgins D. G., Gibson T. J. 1994; clustal w: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 22:4673–4680 [CrossRef]
    [Google Scholar]
  51. Vollmar J., Arndtz N., Eckl K. M., Thomsen T., Petzold B., Mateo L., Schlereth B., Handley A., King L. other authors 2006; Safety and immunogenicity of IMVAMUNE, a promising candidate as a third generation smallpox vaccine. Vaccine 24:2065–2070 [CrossRef]
    [Google Scholar]
  52. Weltzin R., Liu J., Pugachev K. V., Myers G. A., Coughlin B., Blum P. S., Nichols R., Johnson C., Cruz J. other authors 2003; Clonal vaccinia virus grown in cell culture as a new smallpox vaccine. Nat Med 9:1125–1130 [CrossRef]
    [Google Scholar]
  53. Wyatt L. S., Carroll M. W., Czerny C. P., Merchlinsky M., Sisler J. R., Moss B. 1998; Marker rescue of the host range restriction defects of modified vaccinia virus Ankara. Virology 251:334–342 [CrossRef]
    [Google Scholar]
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