1887

Abstract

We report here the complete genome sequence of raccoonpox virus (RCNV), a naturally occurring North American poxvirus. This is the first such North American sequence to the best of our knowledge, and the data showed that RCNV forms a new phylogenetic branch between orthopoxviruses and Yoka poxvirus. RCNV shared overall similarity in genome organization with orthopoxviruses, and the proteins in the central conserved region shared approximately 90  % amino acid identity with orthopoxviruses. RCNV proteins shared approximately 81  % amino acid identity with Yokapox virus proteins. RCNV is missing 10 genes normally conserved in orthopoxviruses, most of which are implicated in virulence. These gene deletions may explain the attenuated phenotype of RCNV in mammals. RCNV contained one unique genome region containing approximately 1 kb of DNA sequence that is not present in any reported poxvirus. It contained a unique ORF predicted to encode a protein with a transmembrane domain. RCNV replicates well in mammalian cells, is naturally attenuated and has been shown to be effective as a vaccine vector platform, so we further tested its safety. We showed here that RCNV is substantially more attenuated than even the highly attenuated VACV-A35Del mutant virus in pregnant, nude and severe combined immunodeficient (SCID) mouse models. RCNV was much safer in pregnant mice and was cleared rapidly from tissues, even in immunocompromised animals, whereas the VACV-A35Del mutant retains virulence and persists in tissues. Thus, RCNV is expected to be a superior vaccine vector for infectious diseases and cancer due to its excellent safety profile, reported vaccine efficacy and ability to replicate in mammalian cells.

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2015-09-01
2020-01-21
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References

  1. Altschul S.F. , Gish W. , Miller W. , Myers E.W. , Lipman D.J. . ( 1990;). Basic local alignment search tool. J Mol Biol 215: 403–410 [CrossRef] [PubMed].
    [Google Scholar]
  2. Altschul S.F. , Madden T.L. , Schäffer 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] [PubMed].
    [Google Scholar]
  3. Belyakov I.M. , Earl P. , Dzutsev A. , Kuznetsov V.A. , Lemon M. , Wyatt L.S. , Snyder J.T. , Ahlers J.D. , other authors . ( 2003;). Shared modes of protection against poxvirus infection by attenuated and conventional smallpox vaccine viruses. Proc Natl Acad Sci USA 100: 9458–9463.[CrossRef]
    [Google Scholar]
  4. Benning N. , Hassett D.E. . ( 2004;). Vaccinia virus infection during murine pregnancy: a new pathogenesis model for vaccinia fetalis. J Virol 78: 3133–3139 [CrossRef] [PubMed].
    [Google Scholar]
  5. Brodie R. , Roper R.L. , Upton C. . ( 2004a;). JDotter: a Java interface to multiple dotplots generated by dotter. Bioinformatics 20: 279–281 [CrossRef] [PubMed].
    [Google Scholar]
  6. Brodie R. , Smith A.J. , Roper R.L. , Tcherepanov V. , Upton C. . ( 2004b;). Base-By-Base: single nucleotide-level analysis of whole viral genome alignments. BMC Bioinformatics 5: 96 [CrossRef] [PubMed].
    [Google Scholar]
  7. Campbell C.T. , Gulley J.L. , Oyelaran O. , Hodge J.W. , Schlom J. , Gildersleeve J.C. . ( 2013;). Serum antibodies to blood group A predict survival on PROSTVAC-VF. Clin Cancer Res 19: 1290–1299 [PubMed].[CrossRef]
    [Google Scholar]
  8. Chen N. , Li G. , Liszewski M.K. , Atkinson J.P. , Jahrling P.B. , Feng Z. , Schriewer J. , Buck C. , Wang C. , other authors . ( 2005;). Virulence differences between monkeypox virus isolates from West Africa and the Congo basin. Virology 340: 46–63 [CrossRef] [PubMed].
    [Google Scholar]
  9. Cottingham M.G. , Carroll M.W. , Recombinant M.V.A. . ( 2013;). vaccines: dispelling the myths. Vaccine 31: 4247–4251 [CrossRef] [PubMed].
    [Google Scholar]
  10. Damaso C.R. , Esposito J.J. , Condit R.C. , Moussatché N. . ( 2000;). An emergent poxvirus from humans and cattle in Rio de Janeiro State: Cantagalo virus may derive from Brazilian smallpox vaccine. Virology 277: 439–449 [CrossRef] [PubMed].
    [Google Scholar]
  11. DeMartini J.C. , Bickle H.M. , Brodie S.J. , He B.X. , Esposito J.J. . ( 1993;). Raccoon poxvirus rabies virus glycoprotein recombinant vaccine in sheep. Arch Virol 133: 211–222 [CrossRef] [PubMed].
    [Google Scholar]
  12. Dhar A.D. , Werchniak A.E. , Li Y. , Brennick J.B. , Goldsmith C.S. , Kline R. , Damon I. , Klaus S.N. . ( 2004;). Tanapox infection in a college student. N Engl J Med 350: 361–366 [CrossRef] [PubMed].
    [Google Scholar]
  13. Earl P.L. , Americo J.L. , Wyatt L.S. , Eller L.A. , Whitbeck J.C. , Cohen G.H. , Eisenberg R.J. , Hartmann C.J. , Jackson D.L. , other authors . ( 2004;). Immunogenicity of a highly attenuated MVA smallpox vaccine and protection against monkeypox. Nature 428: 182–185 [CrossRef] [PubMed].
    [Google Scholar]
  14. Ehlers A. , Osborne J. , Slack S. , Roper R.L. , Upton C. . ( 2002;). Poxvirus orthologous clusters (POCs). Bioinformatics 18: 1544–1545 [CrossRef] [PubMed].
    [Google Scholar]
  15. Emerson G.L. , Li Y. , Frace M.A. , Olsen-Rasmussen M.A. , Khristova M.L. , Govil D. , Sammons S.A. , Regnery R.L. , Karem K.L. , other authors . ( 2009;). The phylogenetics and ecology of the orthopoxviruses endemic to North America. PLoS One 4: e7666 [CrossRef] [PubMed].
    [Google Scholar]
  16. Esposito J.J. . ( 1989;). Live poxvirus-vectored vaccines in wildlife immunization programmes: the rabies paradigm. Res Virol 140: 480–482 discussion 487–491.[CrossRef]
    [Google Scholar]
  17. Evgin L. , Vähä-Koskela M. , Rintoul J. , Falls T. , Le Boeuf F. , Barrett J.W. , Bell J.C. , Stanford M.M. . ( 2010;). Potent oncolytic activity of raccoonpox virus in the absence of natural pathogenicity. Mol Ther 18: 896–902 [CrossRef] [PubMed].
    [Google Scholar]
  18. Fekadu M. , Shaddock J.H. , Sumner J.W. , Sanderlin D.W. , Knight J.C. , Esposito J.J. , Baer G.M. . ( 1991;). Oral vaccination of skunks with raccoon poxvirus recombinants expressing the rabies glycoprotein or the nucleoprotein. J Wildl Dis 27: 681–684 [CrossRef] [PubMed].
    [Google Scholar]
  19. Feldmann F. , Feldmann H. . ( 2013;). Ebola: facing a new transboundary animal disease?. Dev Biol (Basel) 135: 201–209 [PubMed].
    [Google Scholar]
  20. Gallardo-Romero N.F. , Velasco-Villa A. , Weiss S.L. , Emerson G.L. , Carroll D.S. , Hughes C.M. , Li Y. , Karem K.L. , Damon I.K. , Olson V.A. . ( 2011;). Detection of North American orthopoxviruses by real time-PCR. Virol J 8: 313 [PubMed].[CrossRef]
    [Google Scholar]
  21. Gómez C.E. , Nájera J.L. , Krupa M. , Esteban M. . ( 2008;). The poxvirus vectors MVA and NYVAC as gene delivery systems for vaccination against infectious diseases and cancer. Curr Gene Ther 8: 97–120 [PubMed].[CrossRef]
    [Google Scholar]
  22. Guzman E. , Cubillos-Zapata C. , Cottingham M.G. , Gilbert S.C. , Prentice H. , Charleston B. , Hope J.C. . ( 2012;). Modified vaccinia virus Ankara-based vaccine vectors induce apoptosis in dendritic cells draining from the skin via both the extrinsic and intrinsic caspase pathways, preventing efficient antigen presentation. J Virol 86: 5452–5466 [CrossRef] [PubMed].
    [Google Scholar]
  23. Haller S.L. , Peng C. , McFadden G. , Rothenburg S. . ( 2014;). Poxviruses and the evolution of host range and virulence. Infect Genet Evol 21: 15–40 [CrossRef] [PubMed].
    [Google Scholar]
  24. Hatch G.J. , Graham V.A. , Bewley K.R. , Tree J.A. , Dennis M. , Taylor I. , Funnell S.G. , Bate S.R. , Steeds K. , other authors . ( 2013;). Assessment of the protective effect of Imvamune and Acam2000 vaccines against aerosolized monkeypox virus in cynomolgus macaques. J Virol 87: 7805–7815 [CrossRef] [PubMed].
    [Google Scholar]
  25. Hermans E.H. . ( 1964;). [The clinical diagnosis of smallpox and smallpox-like diseases]. Ned Tijdschr Geneeskd 108: 2034–2038 [PubMed] (in Dutch)..
    [Google Scholar]
  26. Hersperger A.R. , Siciliano N.A. , DeHaven B.C. , Snook A.E. , Eisenlohr L.C. . ( 2014;). Epithelial immunization induces polyfunctional CD8+T cells and optimal mousepox protection. J Virol 88: 9472–9475 [PubMed].[CrossRef]
    [Google Scholar]
  27. Hillary W. , Lin S.-H. , Upton C. . ( 2011;). Base-By-Base version 2: single nucleotide-level analysis of whole viral genome alignments. Microb Inform Exp 1: 2 [CrossRef] [PubMed].
    [Google Scholar]
  28. Hirokawa T. , Boon-Chieng S. , Mitaku S. . ( 1998;). sosui: Classification and secondary structure prediction system for membrane proteins. Bioinformatics 14: 378–379 [CrossRef] [PubMed].
    [Google Scholar]
  29. Holmes E.C. , Drummond A.J. . ( 2007;). The evolutionary genetics of viral emergence. Curr Top Microbiol Immunol 315: 51–66 [PubMed].
    [Google Scholar]
  30. Hu L. , Ngichabe C. , Trimarchi C.V. , Esposito J.J. , Scott F.W. . ( 1997;). Raccoon poxvirus live recombinant feline panleukopenia virus VP2 and rabies virus glycoprotein bivalent vaccine. Vaccine 15: 1466–1472 [CrossRef] [PubMed].
    [Google Scholar]
  31. Hui E.P. , Taylor G.S. , Jia H. , Ma B.B.Y. , Chan S.L. , Ho R. , Wong W.-L. , Wilson S. , Johnson B.F. , other authors . ( 2013;). Phase I trial of recombinant modified vaccinia Ankara encoding Epstein-Barr viral tumor antigens in nasopharyngeal carcinoma patients. Cancer Res 73: 1676–1688 [PubMed].[CrossRef]
    [Google Scholar]
  32. Hunter S. , Jones P. , Mitchell A. , Apweiler R. , Attwood T.K. , Bateman A. , Bernard T. , Binns D. , Bork P. , other authors . ( 2012;). InterPro in 2011: new developments in the family and domain prediction database. Nucleic Acids Res 40: (D1), D306–D312 [CrossRef] [PubMed].
    [Google Scholar]
  33. Jones G.J.B. , Boles C. , Roper R.L. . ( 2014;). Raccoonpoxvirus safety in immunocompromised and pregnant mouse models. Vaccine 32: 3977–3981 [CrossRef] [PubMed].
    [Google Scholar]
  34. Jones-Trower A. , Garcia A. , Meseda C.A. , He Y. , Weiss C. , Kumar A. , Weir J.P. , Merchlinsky M. . ( 2005;). Identification and preliminary characterization of vaccinia virus (Dryvax) antigens recognized by vaccinia immune globulin. Virology 343: 128–140 [CrossRef] [PubMed].
    [Google Scholar]
  35. Katoh K. , Standley D.M. . ( 2013;). mafft multiple sequence alignment software version 7: improvements in performance and usability. Mol Biol Evol 30: 772–780 [CrossRef] [PubMed].
    [Google Scholar]
  36. Katoh K. , Asimenos G. , Toh H. . ( 2009;). Multiple alignment of DNA sequences with mafft . Methods Mol Biol 537: 39–64 [PubMed].[CrossRef]
    [Google Scholar]
  37. Kolhapure R.M. , Deolankar R.P. , Tupe C.D. , Raut C.G. , Basu A. , Dama B.M. , Pawar S.D. , Joshi M.V. , Padbidri V.S. , other authors . ( 1997;). Investigation of buffalopox outbreaks in Maharashtra State during 1992-1996. Indian J Med Res 106: 441–446 [PubMed].
    [Google Scholar]
  38. Krogh A. , Larsson B. , von Heijne G. , Sonnhammer E.L. . ( 2001;). Predicting transmembrane protein topology with a hidden Markov model: application to complete genomes. J Mol Biol 305: 567–580 [CrossRef] [PubMed].
    [Google Scholar]
  39. Lederman E.R. , Reynolds M.G. , Karem K. , Braden Z. , Learned-Orozco L.A. , Wassa-Wassa D. , Moundeli O. , Hughes C. , Harvey J. , other authors . ( 2007;). Prevalence of antibodies against orthopoxviruses among residents of Likouala region, Republic of Congo: evidence for monkeypox virus exposure. Am J Trop Med Hyg 77: 1150–1156 [PubMed].
    [Google Scholar]
  40. Lee M.S. , Roos J.M. , McGuigan L.C. , Smith K.A. , Cormier N. , Cohen L.K. , Roberts B.E. , Payne L.G. . ( 1992;). Molecular attenuation of vaccinia virus: mutant generation and animal characterization. J Virol 66: 2617–2630 [PubMed].
    [Google Scholar]
  41. Lewis-Jones S. . ( 2004;). Zoonotic poxvirus infections in humans. Curr Opin Infect Dis 17: 81–89 [CrossRef] [PubMed].
    [Google Scholar]
  42. Lodmell D.L. , Sumner J.W. , Esposito J.J. , Bellini W.J. , Ewalt L.C. . ( 1991;). Raccoon poxvirus recombinants expressing the rabies virus nucleoprotein protect mice against lethal rabies virus infection. J Virol 65: 3400–3405 [PubMed].
    [Google Scholar]
  43. Mahalingam S. , Damon I.K. , Lidbury B.A. . ( 2004;). 25 years since the eradication of smallpox: why poxvirus research is still relevant. Trends Immunol 25: 636–639 [CrossRef] [PubMed].
    [Google Scholar]
  44. McCollum A.M. , Damon I.K. . ( 2014;). Human monkeypox. Clin Infect Dis 58: 260–267.[CrossRef]
    [Google Scholar]
  45. Molino A.C. , Fleischer A.B. Jr , Feldman S.R. . ( 2004;). Patient demographics and utilization of health care services for molluscum contagiosum. Pediatr Dermatol 21: 628–632 [PubMed].[CrossRef]
    [Google Scholar]
  46. Nicholls R.D. , Gray T.A. . ( 2004;). Cellular source of the poxviral N1R/p28 gene family. Virus Genes 29: 359–364 [CrossRef] [PubMed].
    [Google Scholar]
  47. Oliveira D.B. , Assis F.L. , Ferreira P.C. , Bonjardim C.A. , de Souza Trindade G. , Kroon E.G. , Abrahão J.S. . ( 2013;). Group 1 vaccinia virus zoonotic outbreak in Maranhao State, Brazil. Am J Trop Med Hyg 89: 1142–1145 [CrossRef] [PubMed].
    [Google Scholar]
  48. Osorio J.E. , Frank R.S. , Moss K. , Taraska T. , Powell T. , Stinchcomb D.T. . ( 2003a;). Raccoon poxvirus as a mucosal vaccine vector for domestic cats. J Drug Target 11: 463–470 [CrossRef] [PubMed].
    [Google Scholar]
  49. Osorio J.E. , Powell T.D. , Frank R.S. , Moss K. , Haanes E.J. , Smith S.R. , Rocke T.E. , Stinchcomb D.T. . ( 2003b;). Recombinant raccoon pox vaccine protects mice against lethal plague. Vaccine 21: 1232–1238 [CrossRef] [PubMed].
    [Google Scholar]
  50. Petersen T.N. , Brunak S. , von Heijne G. , Nielsen H. . ( 2011;). SignalP 4.0: discriminating signal peptides from transmembrane regions. Nat Methods 8: 785–786 [CrossRef] [PubMed].
    [Google Scholar]
  51. Rehm K.E. , Roper R.L. . ( 2011;). Deletion of the A35 gene from modified vaccinia virus Ankara increases immunogenicity and isotype switching. Vaccine 29: 3276–3283 [CrossRef] [PubMed].
    [Google Scholar]
  52. Rehm K.E. , Jones G.J.B. , Tripp A.A. , Metcalf M.W. , Roper R.L. . ( 2010a;). The poxvirus A35 protein is an immunoregulator. J Virol 84: 418–425 [PubMed].[CrossRef]
    [Google Scholar]
  53. Rehm K.E. , Connor R.F. , Jones G.J.B. , Yimbu K. , Roper R.L. . ( 2010b;). Vaccinia virus A35R inhibits MHC class II antigen presentation. Virology 397: 176–186 [CrossRef] [PubMed].
    [Google Scholar]
  54. Rerks-Ngarm S. , Pitisuttithum P. , Nitayaphan S. , Kaewkungwal J. , Chiu J. , Paris R. , Premsri N. , Namwat C. , de Souza M. , other authors . ( 2009;). Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med 361: 2209–2220 [CrossRef] [PubMed].
    [Google Scholar]
  55. Roper R.L. . ( 2006;). Characterization of the vaccinia virus A35R protein and its role in virulence. J Virol 80: 306–313 [PubMed].[CrossRef]
    [Google Scholar]
  56. Saitou N. , Nei M. . ( 1987;). The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol Biol Evol 4: 406–425 [PubMed].
    [Google Scholar]
  57. Senkevich T.G. , Koonin E.V. , Bugert J.J. , Darai G. , Moss B. . ( 1997;). The genome of molluscum contagiosum virus: analysis and comparison with other poxviruses. Virology 233: 19–42 [CrossRef] [PubMed].
    [Google Scholar]
  58. Shchelkunov S.N. . ( 2013;). An increasing danger of zoonotic orthopoxvirus infections. PLoS Pathog 9: e1003756.[CrossRef]
    [Google Scholar]
  59. Smith G.L. , Benfield C.T.O. , Maluquer de Motes C. , Mazzon M. , Ember S.W.J. , Ferguson B.J. , Sumner R.P. . ( 2013;). Vaccinia virus immune evasion: mechanisms, virulence and immunogenicity. J Gen Virol 94: 2367–2392 [PubMed].[CrossRef]
    [Google Scholar]
  60. Stich A. , Meyer H. , Köhler B. , Fleischer K. . ( 2002;). Tanapox: first report in a European traveller and identification by PCR. Trans R Soc Trop Med Hyg 96: 178–179 [CrossRef] [PubMed].
    [Google Scholar]
  61. Tamura K. , Peterson D. , Peterson N. , Stecher G. , Nei M. , Kumar S. . ( 2011;). mega5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol Biol Evol 28: 2731–2739 [CrossRef] [PubMed].
    [Google Scholar]
  62. Tcherepanov V. , Ehlers A. , Upton C. . ( 2006;). Genome Annotation Transfer Utility (GATU): rapid annotation of viral genomes using a closely related reference genome. BMC Genomics 7: 150 [CrossRef] [PubMed].
    [Google Scholar]
  63. Tscharke D.C. , Karupiah G. , Zhou J. , Palmore T. , Irvine K.R. , Haeryfar S.M.M. , Williams S. , Sidney J. , Sette A. , other authors . ( 2005;). Identification of poxvirus CD8+T cell determinants to enable rational design and characterization of smallpox vaccines. J Exp Med 201: 95–104 [PubMed].[CrossRef]
    [Google Scholar]
  64. Tusnády G.E. , Simon I. . ( 2001;). The HMMTOP transmembrane topology prediction server. Bioinformatics 17: 849–850 [CrossRef] [PubMed].
    [Google Scholar]
  65. Upton C. , Hogg D. , Perrin D. , Boone M. , Harris N.L. . ( 2000;). Viral genome organizer: a system for analyzing complete viral genomes. Virus Res 70: 55–64 [CrossRef] [PubMed].
    [Google Scholar]
  66. Upton C. , Slack S. , Hunter A.L. , Ehlers A. , Roper R.L. . ( 2003;). Poxvirus orthologous clusters: toward defining the minimum essential poxvirus genome. J Virol 77: 7590–7600 [CrossRef] [PubMed].
    [Google Scholar]
  67. Wasmoen T.L. , Kadakia N.P. , Unfer R.C. , Fickbohm B.L. , Cook C.P. , Chu H.J. , Acree W.M. . ( 1995;). Protection of cats from infectious peritonitis by vaccination with a recombinant raccoon poxvirus expressing the nucleocapsid gene of feline infectious peritonitis virus. Adv Exp Med Biol 380: 221–228 [PubMed].[CrossRef]
    [Google Scholar]
  68. 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] [PubMed].
    [Google Scholar]
  69. Ye J. , McGinnis S. , Madden T.L. . ( 2006;). blast: improvements for better sequence analysis. Nucleic Acids Res 34: W6–W9 [CrossRef] [PubMed].
    [Google Scholar]
  70. Zhao G. , Droit L. , Tesh R.B. , Popov V.L. , Little N.S. , Upton C. , Virgin H.W. , Wang D. . ( 2011;). The genome of Yoka poxvirus. J Virol 85: 10230–10238 [CrossRef] [PubMed].
    [Google Scholar]
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