1887

Abstract

Studies with a murine cytomegalovirus mutant suggested two possible approaches to producing a live attenuated human cytomegalovirus vaccine. One approach would be to use a combination of five to six mutants where an attenuating mutation in the gene of one mutant is compensated by the wild-type version in a second mutant, which in turn has a mutation in a different gene compensated by the wild-type version in a third mutant, etc. Important genes in this approach could include those involved in DNA replication. The importance of the carboxy terminase of the primase gene (M70/UL70) for its function suggested a second approach where some of the natural codons in this region could be substituted with synonymous non-preferred (minor) codons that would reduce the replication fitness of the mutant.

Funding
This study was supported by the:
  • Not Applicable , none , (Award none)
Loading

Article metrics loading...

/content/journal/acmi/10.1099/acmi.0.000147
2020-06-22
2020-10-24
Loading full text...

Full text loading...

/deliver/fulltext/acmi/2/9/acmi000147.html?itemId=/content/journal/acmi/10.1099/acmi.0.000147&mimeType=html&fmt=ahah

References

  1. Mocarski ES, Shenk T, Griffith P, Pass RF. Cytomegaloviruses . In Knipe DM, Howley PM. eds Field’s Virology, 6th edn. Lipincott Williams and Wilkins; 2013 pp 1960–2014
    [Google Scholar]
  2. Krause PR, Bialek SR, Boppana SB, Griffiths PD, Laughlin CA et al. Priorities for CMV vaccine development. Vaccine 2013; 32:4–10 [CrossRef]
    [Google Scholar]
  3. Arvin AM, Fast P, Myers M, Plotkin S, Rabinovich R et al. Vaccine development to prevent cytomegalovirus disease: report from the National Vaccine Advisory Committee. Clin Infect Dis 2004; 39:233–239 [CrossRef][PubMed]
    [Google Scholar]
  4. Sung H, Schleiss MR. Update on the current status of cytomegalovirus vaccines. Expert Rev Vaccines 2010; 9:1303–1314 [CrossRef][PubMed]
    [Google Scholar]
  5. Schleiss MR. Developing a vaccine against congenital cytomegalovirus (CMV) infection: what have we learned from animal models? Where should we go next?. Future Virol 2013; 8:1161–1182 [CrossRef][PubMed]
    [Google Scholar]
  6. Nelson CS, Herold BC, Permar SR. A new era in cytomegalovirus vaccinology: considerations for rational design of next-generation vaccines to prevent congenital cytomegalovirus infection. NPJ Vaccines 2018; 3:38 [CrossRef]
    [Google Scholar]
  7. Krause PR, Klinman DM. Efficacy, immunogenicity, safety, and use of live attenuated chickenpox vaccine. J Pediatr 1995; 127:518–525 [CrossRef][PubMed]
    [Google Scholar]
  8. Oxman MN, Levin MJ, Johnson GR, Schmader KE, Straus SE et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005; 352:2271–2284 [CrossRef][PubMed]
    [Google Scholar]
  9. Depledge DP, Yamanishi K, Gomi Y, Gershon AA, Breuer J. Deep sequencing of distinct preparations of the live attenuated varicella-zoster virus vaccine reveals a conserved core of attenuating single-nucleotide polymorphisms. J Virol 2016; 90:8698–8704 [CrossRef][PubMed]
    [Google Scholar]
  10. Sweet C. The pathogenicity of cytomegalovirus. FEMS Microbiol Rev 1999; 23:457–482 [CrossRef][PubMed]
    [Google Scholar]
  11. Sammons CC, Sweet C. Isolation and preliminary characterization of temperature-sensitive mutants of mouse cytomegalovirus of differing virulence for 1-week-old mice. J Gen Virol 1989; 70:2373–2381 [CrossRef][PubMed]
    [Google Scholar]
  12. Akel HM, Furarah AM, Sweet C. Further studies of 31 temperature-sensitive mutants of mouse cytomegalovirus: thermal stability, replication and analysis of temperature-sensitive functions by temperature shift. FEMS Microbiol Lett 1993; 114:311–316 [CrossRef][PubMed]
    [Google Scholar]
  13. Furrarah AM, Sweet C. Studies of the pathogenesis of wild-type virus and six temperature-sensitive mutants of mouse cytomegalovirus. J Med Virol 1994; 43:317–330 [CrossRef][PubMed]
    [Google Scholar]
  14. Bevan IS, Sammons CC, Sweet C. Investigation of murine cytomegalovirus latency and reactivation in mice using viral mutants and the polymerase chain reaction. J Med Virol 1996; 48:308–320 [CrossRef][PubMed]
    [Google Scholar]
  15. Morley PJ, Ertl P, Sweet C. Immunisation of BALB/c mice with severely attenuated murine cytomegalovirus mutants induces protective cellular and humoral immunity. J Med Virol 2002; 67:187–199 [CrossRef][PubMed]
    [Google Scholar]
  16. Timoshenko O, Al-Ali A, Martin BAB, Sweet C. Identification of mutations in a temperature-sensitive mutant (tsm 5) of murine cytomegalovirus using complementary genome sequencing. J Med Virol 2009; 81:511–518 [CrossRef][PubMed]
    [Google Scholar]
  17. Sweet C, Ball K, Morley PJ, Guilfoyle K, Kirby M. Mutations in the temperature-sensitive murine cytomegalovirus (MCMV) mutants tsm 5 and tsm 30: a study of genes involved in immune evasion, DNA packaging and processing, and DNA replication. J Med Virol 2007; 79:285–299 [CrossRef][PubMed]
    [Google Scholar]
  18. Timoshenko O, Al-Ali A, Martin BAB, Sweet C. Role of mutations identified in ORFs M56 (terminase), M70 (primase) and M98 (endonuclease) in the temperature-sensitive phenotype of murine cytomegalovirus mutant tsm5. Virology 2009; 392:114–122 [CrossRef][PubMed]
    [Google Scholar]
  19. Al-Ali AT, Sweet C. Further studies on the role of the residue 890 cysteine to tyrosine mutation in the M70 primase ORF of the temperature-sensitive mutant (tsm 5) of murine cytomegalovirus. J Med Virol 2016; 88:1613–1621 [CrossRef][PubMed]
    [Google Scholar]
  20. Timoshenko O. Role of mutations identified in the M56, M70 and M98 genes of the murine cytomegalovirus (MCMV) temperature-sensitive mutant tsm5. PhD Thesis Birmingham University, UK; 2009
    [Google Scholar]
  21. Ligat G, Da Re S, Alain S, Hantz S. Identification of amino acids essential for viral replication in the HCMV helicase-primase complex. Front Microbiol 2018; 9:2483 [CrossRef][PubMed]
    [Google Scholar]
  22. Al-Ali A, Timoshenko O, Martin BAB, Sweet C. Role of mutations identified in ORFs M27, M36, m139, m141, and m143 in the temperature-sensitive phenotype of murine cytomegalovirus mutant tsm 5. J Med Virol 2012; 84:912–922 [CrossRef][PubMed]
    [Google Scholar]
  23. Gustafsson C, Govindarajan S, Minshull J. Codon bias and heterologous protein expression. Trends Biotechnol 2004; 22:346–353 [CrossRef][PubMed]
    [Google Scholar]
  24. Burns CC, Shaw J, Campagnoli R, Jorba J, Vincent A et al. Modulation of poliovirus replicative fitness in HeLa cells by deoptimization of synonymous codon usage in the capsid region. J Virol 2006; 80:3259–3272 [CrossRef][PubMed]
    [Google Scholar]
  25. Mueller S, Papamichail D, Coleman JR, Skiena S, Wimmer E. Reduction of the rate of poliovirus protein synthesis through large-scale codon deoptimization causes attenuation of viral virulence by lowering specific infectivity. J Virol 2006; 80:9687–9696 [CrossRef][PubMed]
    [Google Scholar]
  26. Klitting R, Riziki T, Moureau G, Piorkowski G, Gould EA et al. Exploratory re-encoding of yellow fever virus genome: new insights for the design of live-attenuated viruses. Virus Evol 2018; 4:vey021 [CrossRef][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/acmi/10.1099/acmi.0.000147
Loading

Most cited this month Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error