1887

Abstract

The immediate-early 1 (IE1) and IE2 proteins encoded by the major immediate-early (MIE) transcription unit of cytomegaloviruses are thought to play key roles in the switch between latent- and lytic-cycle infection. Whilst IE2 is essential for triggering the lytic cycle, the exact roles of IE1 have not been resolved. An MIE–exon 4-deleted rat cytomegalovirus (ΔIE1) failed to synthesize the IE1 protein and did not disperse promyelocytic leukaemia bodies early post-infection, but was still capable of normal replication in fibroblast cell culture. However, ΔIE1 had a diminished ability to infect salivary glands persistently and to reactivate from spleen explant cultures . Quantification of viral genomes in spleens of infected animals revealed a reduced amount of ΔIE1 virus produced during acute infection, suggesting a role for IE1 as a regulator in establishing a chronic or persistent infection, rather than in influencing the latency or reactivation processes more directly.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.016022-0
2010-03-01
2019-11-14
Loading full text...

Full text loading...

/deliver/fulltext/jgv/91/3/616.html?itemId=/content/journal/jgv/10.1099/vir.0.016022-0&mimeType=html&fmt=ahah

References

  1. Ahn, J. H. & Hayward, G. S. ( 1997; ). The major immediate-early proteins IE1 and IE2 of human cytomegalovirus colocalize with and disrupt PML-associated nuclear bodies at very early times in infected permissive cells. J Virol 71, 4599–4613.
    [Google Scholar]
  2. Ahn, J. H. & Hayward, G. S. ( 2000; ). Disruption of PML-associated nuclear bodies by IE1 correlates with efficient early stages of viral gene expression and DNA replication in human cytomegalovirus infection. Virology 274, 39–55.[CrossRef]
    [Google Scholar]
  3. Ahn, J. H., Brignole, E. J., III & Hayward, G. S. ( 1998; ). Disruption of PML subnuclear domains by the acidic IE1 protein of human cytomegalovirus is mediated through interaction with PML and may modulate a RING finger-dependent cryptic transactivator function of PML. Mol Cell Biol 18, 4899–4913.
    [Google Scholar]
  4. 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.[CrossRef]
    [Google Scholar]
  5. Busche, A., Marquardt, A., Bleich, A., Ghazal, P., Angulo, A. & Messerle, M. ( 2009; ). The mouse cytomegalovirus immediate-early 1 gene is not required for establishment of latency or for reactivation in the lungs. J Virol 83, 4030–4038.[CrossRef]
    [Google Scholar]
  6. Ghazal, P., Visser, A. E., Gustems, M., Garcia, R., Borst, E. M., 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.[CrossRef]
    [Google Scholar]
  7. Greaves, R. F. & Mocarski, E. S. ( 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.
    [Google Scholar]
  8. Honess, R. W., Gompels, U. A., Barrell, B. G., Craxton, M., Cameron, K. R., Staden, R., Chang, Y. N. & Hayward, G. S. ( 1989; ). Deviations from expected frequencies of CpG dinucleotides in herpesvirus DNAs may be diagnostic of differences in the states of their latent genomes. J Gen Virol 70, 837–855.[CrossRef]
    [Google Scholar]
  9. Huh, Y. H., Kim, Y. E., Kim, E. T., Park, J. J., Song, M. J., Zhu, H., Hayward, G. S. & Ahn, J. H. ( 2008; ). Binding STAT2 by the acidic domain of human cytomegalovirus IE1 promotes viral growth and is negatively regulated by SUMO. J Virol 82, 10444–10454.[CrossRef]
    [Google Scholar]
  10. Keil, G. M., Ebeling-Keil, A. & Koszinowski, U. H. ( 1987; ). Sequence and structural organization of murine cytomegalovirus immediate-early gene 1. J Virol 61, 1901–1908.
    [Google Scholar]
  11. Lafemina, R. L., Pizzorno, M. C., Mosca, J. D. & Hayward, G. S. ( 1989; ). Expression of the acidic nuclear immediate-early protein (IE1) of human cytomegalovirus in stable cell lines and its preferential association with metaphase chromosomes. Virology 172, 584–600.[CrossRef]
    [Google Scholar]
  12. Lee, H. R., Kim, D. J., Lee, J. M., Choi, C. Y., Ahn, B. Y., Hayward, G. S. & Ahn, J. H. ( 2004; ). Ability of the human cytomegalovirus IE1 protein to modulate sumoylation of PML correlates with its functional activities in transcriptional regulation and infectivity in cultured fibroblast cells. J Virol 78, 6527–6542.[CrossRef]
    [Google Scholar]
  13. 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.[CrossRef]
    [Google Scholar]
  14. Meier, J. L. & Stinski, M. F. ( 2006; ). Major immediate-early enhancer and its gene products. In Cytomegaloviruses: Molecular Biology and Immunology, pp. 151–166. Edited by M. J. Reddehase. Wymondham, UK: Caister Academic Press.
  15. Messerle, M., Buhler, B., Keil, G. M. & Koszinowski, U. H. ( 1992; ). Structural organization, expression, and functional characterization of the murine cytomegalovirus immediate-early gene 3. J Virol 66, 27–36.
    [Google Scholar]
  16. Mocarski, E. S., Kemble, G. W., Lyle, J. M. & Greaves, R. F. ( 1996; ). A deletion mutant in the human cytomegalovirus gene encoding IE1(491aa) is replication defective due to a failure in autoregulation. Proc Natl Acad Sci U S A 93, 11321–11326.[CrossRef]
    [Google Scholar]
  17. Mocarski, E. S., Shenk, T. & Pass, R. F. ( 2007; ). Cytomegaloviruses. In Fields Virology, 5th edn, pp. 2701–2772. Edited by D. M. Knipe & P. M. Howley. Philadelphia, PA: Lippincott Williams & Wilkins.
  18. Nevels, M., Brune, W. & Shenk, T. ( 2004; ). SUMOylation of the human cytomegalovirus 72-kilodalton IE1 protein facilitates expression of the 86-kilodalton IE2 protein and promotes viral replication. J Virol 78, 7803–7812.[CrossRef]
    [Google Scholar]
  19. Reddehase, M. J., Balthesen, M., Rapp, M., Jonjic, S., Pavic, I. & Koszinowski, U. H. ( 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.[CrossRef]
    [Google Scholar]
  20. Reddehase, M. J., Podlech, J. & Grzimek, N. K. ( 2002; ). Mouse models of cytomegalovirus latency: overview. J Clin Virol 25, (Suppl. 2), S23–S36.
    [Google Scholar]
  21. Reddehase, M. J., Simon, C. O., Seckert, C. K., Lemmermann, N. & Grzimek, N. K. ( 2008; ). Murine model of cytomegalovirus latency and reactivation. Curr Top Microbiol Immunol 325, 315–331.
    [Google Scholar]
  22. Sandford, G. R., Ho, K. & Burns, W. H. ( 1993; ). Characterization of the major locus of immediate-early genes of rat cytomegalovirus. J Virol 67, 4093–4103.
    [Google Scholar]
  23. Sandford, G. R., Brock, L. E., Voigt, S., Forester, C. M. & Burns, W. H. ( 2001; ). Rat cytomegalovirus major immediate-early enhancer switching results in altered growth characteristics. J Virol 75, 5076–5083.[CrossRef]
    [Google Scholar]
  24. Simon, C. O., Seckert, C., Grzimek, N. K. & Reddehase, M. J. ( 2006; ). Murine model of cytomegalovirus latency and reactivation: the silencing/desilencing and immune sensing hypothesis. In Cytomegaloviruses: Molecular Biology and Immunology, pp. 483–500. Edited by M. J. Reddehase. Wymondham, UK: Caister Academic Press.
  25. Stinski, M. F. & Isomura, H. ( 2008; ). Role of the cytomegalovirus major immediate early enhancer in acute infection and reactivation from latency. Med Microbiol Immunol 197, 223–231.[CrossRef]
    [Google Scholar]
  26. Stinski, M. F., Thomsen, D. R., Stenberg, R. M. & Goldstein, L. C. ( 1983; ). Organization and expression of the immediate early genes of human cytomegalovirus. J Virol 46, 1–14.
    [Google Scholar]
  27. Tang, Q. & Maul, G. G. ( 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.[CrossRef]
    [Google Scholar]
  28. Tavalai, N., Papior, P., Rechter, S., Leis, M. & Stamminger, T. ( 2006; ). Evidence for a role of the cellular ND10 protein PML in mediating intrinsic immunity against human cytomegalovirus infections. J Virol 80, 8006–8018.[CrossRef]
    [Google Scholar]
  29. Voigt, S., Mesci, A., Ettinger, J., Fine, J. H., Chen, P., Chou, W. & Carlyle, J. R. ( 2007; ). Cytomegalovirus evasion of innate immunity by subversion of the NKR-P1B : Clr-b missing-self axis. Immunity 26, 617–627.[CrossRef]
    [Google Scholar]
  30. White, E. A., Clark, C. L., Sanchez, V. & Spector, D. H. ( 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.[CrossRef]
    [Google Scholar]
  31. Wilhelmi, V., Simon, C. O., Podlech, J., Bohm, V., Daubner, T., Emde, S., Strand, D., Renzaho, A., Lemmermann, N. A. & other authors ( 2008; ). Transactivation of cellular genes involved in nucleotide metabolism by the regulatory IE1 protein of murine cytomegalovirus is not critical for viral replicative fitness in quiescent cells and host tissues. J Virol 82, 9900–9916.[CrossRef]
    [Google Scholar]
  32. Wilkinson, G. W., Kelly, C., Sinclair, J. H. & Rickards, C. ( 1998; ). Disruption of PML-associated nuclear bodies mediated by the human cytomegalovirus major immediate early gene product. J Gen Virol 79, 1233–1245.
    [Google Scholar]
  33. Xu, Y., Ahn, J. H., Cheng, M., apRhys, C. M., Chiou, C. J., Zong, J., Matunis, M. J. & Hayward, G. S. ( 2001; ). Proteasome-independent disruption of PML oncogenic domains (PODs), but not covalent modification by SUMO-1, is required for human cytomegalovirus immediate-early protein IE1 to inhibit PML-mediated transcriptional repression. J Virol 75, 10683–10695.[CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.016022-0
Loading
/content/journal/jgv/10.1099/vir.0.016022-0
Loading

Data & Media loading...

Supplements

vol. , part 3, pp. 616–621

Southern blot analysis to measure the equivalency of p.f.u. : particle ratios

PCR analysis to verify the integrity of exons 3 and 5 in ΔIE1ex4

PCR analysis to detect viral DNA in animals infected with ΔIE1ex4

Representative Western blot of virus isolated from salivary gland or reactivated from spleen from persistently (120 days) infected animals

[ Single PDF file] (275 KB)



PDF

Most Cited This Month

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