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Phenotypes of major immediate-early gene mutants of mouse cytomegalovirus

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Abstract

Immediate-early (IE) genes are the first genes to be transcribed during the lytic replication cycle of cytomegaloviruses (CMV), and encode nonstructural proteins, which are assumed to have mainly regulatory functions. The IE proteins may play important roles in the pathogenesis of CMV in vivo, for instance during the establishment of latency and during reactivation. We constructed mouse CMV mutants with disruptions in the major IE genes, ie1 and ie3, to study the roles of these genes in the context of the viral infection. Here we summarize the current results on the characterization of these mutants and give a perspective of the future research in this field.

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References

  1. Mocarski ES, Courcelle CT (2001) Cytomegaloviruses and their replication. In: Knipe DM, Howley PM (eds) Fields virology. Lippincott Williams & Wilkins, Philadelphia, pp 2629–2674

    Google Scholar 

  2. Meier JL, Stinski MF (2006) Major immediate-early enhancer and its gene products. In: Reddehase MJ (ed) Cytomegaloviruses: molecular biology and immunology. Caister Academic Press, Wymondham, pp 151–166

    Google Scholar 

  3. Messerle M, Bühler B, Keil GM, Koszinowski UH (1992) Structural organization, expression, and functional characterization of the murine cytomegalovirus immediate-early gene 3. J Virol 66:27–36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wiebusch L, Hagemeier C (2001) The human cytomegalovirus immediate early 2 protein dissociates cellular DNA synthesis from cyclin-dependent kinase activation. EMBO J 20:1086–1098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Stenberg RM, Stinski MF (1985) Autoregulation of the human cytomegalovirus major immediate-early gene. J Virol 56:676–682

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cherrington JM, Mocarski ES (1989) Human cytomegalovirus ie1 transactivates the alpha promoter-enhancer via an 18-base-pair repeat element. J Virol 63:1435–1440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Stenberg RM, Fortney J, Barlow SW, Magrane BP, Nelson JA, Ghazal P (1990) Promoter-specific trans activation and repression by human cytomegalovirus immediate-early proteins involves common and unique protein domains. J Virol 64:1556–1565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Margolis MJ, Pajovic S, Wong EL, Wade M, Jupp R, Nelson JA, Azizkhan JC (1995) Interaction of the 72-kilodalton human cytomegalovirus IE1 gene product with E2F1 coincides with E2F-dependent activation of dihydrofolate reductase transcription. J Virol 69:7759–7767

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gribaudo G, Riera L, Lembo D, De Andrea M, Gariglio M, Rudge TL, Johnson LF, Landolfo S (2000) Murine cytomegalovirus stimulates cellular thymidylate synthase gene expression in quiescent cells and requires the enzyme for replication. J Virol 74:4979–4987

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Tang Q, Maul GG (2006) Immediate-early interactions and epigenetic defense mechanisms. In: Reddehase MJ (ed) Cytomegaloviruses: molecular biology and immunology. Caister Academic Press, Wymondham, pp 131–149

    Google Scholar 

  11. Nevels M, Paulus C, Shenk T (2004) Human cytomegalovirus immediate-early 1 protein facilitates viral replication by antagonizing histone deacetylation. Proc Natl Acad Sci U S A 101:17234–17239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Tang Q, Maul GG (2003) Mouse cytomegalovirus immediate-early protein 1 binds with host cell repressors to relieve suppressive effects on viral transcription and replication during lytic infection. J Virol 77:1357–1367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Greaves RF, Mocarski ES (1998) Defective growth correlates with reduced accumulation of a viral DNA replication protein after low-multiplicity infection by a human cytomegalovirus ie1 mutant. J Virol 72:366–379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Paulus C, Krauss S, Nevels M (2006) A human cytomegalovirus antagonist of type I IFN-dependent signal transducer and activator of transcription signaling. Proc Natl Acad Sci U S A 103:3840–3845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Voigt S, Sandford GR, Hayward GS, Burns WH (2005) The English strain of rat cytomegalovirus (CMV) contains a novel captured CD200 (vOX2) gene and a spliced CC chemokine upstream from the major immediate-early region: further evidence for a separate evolutionary lineage from that of rat CMV Maastricht. J Gen Virol 86:263–274

    Article  CAS  PubMed  Google Scholar 

  16. Grzimek NK, Dreis D, Schmalz S, Reddehase MJ (2001) Random, asynchronous, and asymmetric transcriptional activity of enhancer-flanking major immediate-early genes ie1/3 and ie2 during murine cytomegalovirus latency in the lungs. J Virol 75:2692–2705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Cardin RD, Abenes GB, Stoddart CA, Mocarski ES (1995) Murine cytomegalovirus IE2, an activator of gene expression, is dispensable for growth and latency in mice. Virology 209:236–241

    Article  CAS  PubMed  Google Scholar 

  18. Messerle M, Crnkovic I, Hammerschmidt W, Ziegler H, Koszinowski UH (1997) Cloning and mutagenesis of a herpesvirus genome as an infectious bacterial artificial chromosome. Proc Natl Acad Sci USA 94:14759–14763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Borst EM, Hahn G, Koszinowski UH, Messerle M (1999) Cloning of the human cytomegalovirus (HCMV) genome as an infectious bacterial artificial chromosome in Escherichia coli: a new approach for construction of HCMV mutants. J Virol 73:8320–8329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Angulo A, Ghazal P, Messerle M (2000) The major immediate-early gene ie3 of mouse cytomegalovirus is essential for viral growth. J Virol 74:11129–11136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Marchini A, Liu H, Zhu H (2001) Human cytomegalovirus with IE-2 (UL122) deleted fails to express early lytic genes. J Virol 75:1870–1878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Heider JA, Bresnahan WA, Shenk TE (2002) Construction of a rationally designed human cytomegalovirus variant encoding a temperature-sensitive immediate-early 2 protein. Proc Natl Acad Sci U S A 99:3141–3146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. White EA, Clark CL, Sanchez V, Spector DH (2004) Small internal deletions in the human cytomegalovirus IE2 gene result in nonviable recombinant viruses with differential defects in viral gene expression. J Virol 78:1817–1830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Pollock R, Clackson T (2002) Dimerizer-regulated gene expression. Curr Opin Biotechnol 13:459–467

    Article  CAS  PubMed  Google Scholar 

  25. Feil R, Wagner J, Metzger D, Chambon P (1997) Regulation of Cre recombinase activity by mutated estrogen receptor ligand-binding domains. Biochem Biophys Res Commun 237:752–757

    Article  CAS  PubMed  Google Scholar 

  26. Ghazal P, Visser AE, Gustems M, Garcia R, Borst EM, Sullivan K, Messerle M, Angulo A (2005) Elimination of ie1 significantly attenuates murine cytomegalovirus virulence but does not alter replicative capacity in cell culture. J Virol 79:7182–7194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gawn JM, Greaves RF (2002) Absence of IE1 p72 protein function during low-multiplicity infection by human cytomegalovirus results in a broad block to viral delayed-early gene expression. J Virol 76:4441–4455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Reddehase MJ, Balthesen M, Rapp M, Jonjic S, Pavic I, Koszinowski UH (1994) The conditions of primary infection define the load of latent viral genome in organs and the risk of recurrent cytomegalovirus disease. J Exp Med 179:185–193

    Article  CAS  PubMed  Google Scholar 

  29. Tatusova TA, Madden TL (1999) BLAST 2 sequences, a new tool for comparing protein and nucleotide sequences. FEMS Microbiol Lett 174:247–250

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Our work is supported by grants of the German Research Council (DFG; collaborative research grant 587, individual project A13 to M.M.), of the Ministerio de Ciencia y Tecnología (MCYT; SAF2005-05633 to A.A.) and of the Wellcome Trust (to P.G.).

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Authors and Affiliations

  1. Department of Virology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany

    Andreas Busche, Penelope Kay-Jackson & Martin Messerle

  2. Institut d’Investigacions Biomédiques August Pi I Sunyer, 08036, Barcelona, Spain

    Ana Angulo

  3. Division of Pathway Medicine, University of Edinburgh, Edinburgh, EH16 4SB, UK

    Peter Ghazal

Authors
  1. Andreas Busche
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  2. Ana Angulo
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  3. Penelope Kay-Jackson
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  4. Peter Ghazal
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  5. Martin Messerle
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Correspondence to Martin Messerle.

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Busche, A., Angulo, A., Kay-Jackson, P. et al. Phenotypes of major immediate-early gene mutants of mouse cytomegalovirus. Med Microbiol Immunol 197, 233–240 (2008). https://doi.org/10.1007/s00430-008-0076-3

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  • DOI: https://doi.org/10.1007/s00430-008-0076-3

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