1887

Abstract

Human herpesvirus 6B (HHV-6B) induces significant accumulation of p53 in both the nucleus and cytoplasm during infection. Activation of p53 by DNA damage is known to induce either growth arrest or apoptosis; nevertheless, HHV-6B-infected cells are arrested in their cell cycle independently of p53, and only a minor fraction of the infected cells undergoes apoptosis. Using pifithrin-, a p53 inhibitor, and p53-null cells, this study showed that infected epithelial cells accumulated viral transcripts and proteins to a significantly higher degree in the absence of active p53. Moreover, HHV-6B-induced cytopathic effects were greatly enhanced in the absence of p53. This suggests that, in epithelial cells, some of the functions of p53 leading to cell-cycle arrest and apoptosis are restrained by HHV-6B infection, whereas other cellular defences, causing inhibition of virus transcription, are partially retained.

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2008-05-01
2020-10-29
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References

  1. Black J. B., Lopez C., Pellett P. E. 1992; Induction of host cell protein synthesis by human herpesvirus 6. Virus Res 22:13–23 [CrossRef]
    [Google Scholar]
  2. Boutell C., Everett R. D. 2004; Herpes simplex virus type 1 infection induces the stabilization of p53 in a USP7- and ATM-independent manner. J Virol 78:8068–8077 [CrossRef]
    [Google Scholar]
  3. Boutolleau D., Duros C., Bonnafous P., Caïola D., Karras A., Castro N. D., Ouachée M., Narcy P., Gueudin M. other authors 2006; Identification of human herpesvirus 6 variants A and B by primer-specific real-time PCR may help to revisit their respective role in pathology. J Clin Virol 35:257–263 [CrossRef]
    [Google Scholar]
  4. Braun D. K., Dominguez G., Pellett P. E. 1997; Human herpesvirus 6. Clin Microbiol Rev 10:521–567
    [Google Scholar]
  5. Bunz F., Dutriaux A., Lengauer C., Waldman T., Zhou S., Brown J. P., Sedivy J. M., Kinzler K. W., Vogelstein B. 1998; Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 282:1497–1501 [CrossRef]
    [Google Scholar]
  6. Casavant N. C., Luo M. H., Rosenke K., Winegardner T., Zurawska A., Fortunato E. A. 2006; Potential role of p53 in the permissive life cycle of human cytomegalovirus. J Virol 80:8390–8401 [CrossRef]
    [Google Scholar]
  7. De Bolle L., Hatse S., Verbeken E., De C. E., Naesens L. 2004; Human herpesvirus 6 infection arrests cord blood mononuclear cells in G2 phase of the cell cycle. FEBS Lett 560:25–29 [CrossRef]
    [Google Scholar]
  8. Di Luca D., Katsafanas G., Schirmer E. C., Balachandran N., Frenkel N. 1990; The replication of viral and cellular DNA in human herpesvirus 6-infected cells. Virology 175:199–210 [CrossRef]
    [Google Scholar]
  9. Donati D., Martinelli E., Cassiani-Ingoni R., Ahlqvist J., Hou J., Major E. O., Jacobson S. 2005; Variant-specific tropism of human herpesvirus 6 in human astrocytes. J Virol 79:9439–9448 [CrossRef]
    [Google Scholar]
  10. Fortunato E. A., Spector D. H. 1998; p53 and RPA are sequestered in viral replication centers in the nuclei of cells infected with human cytomegalovirus. J Virol 72:2033–2039
    [Google Scholar]
  11. Hall C. B., Caserta M. T., Schnabel K. C., Long C., Epstein L. G., Insel R. A., Dewhurst S. 1998; Persistence of human herpesvirus 6 according to site and variant: possible greater neurotropism of variant A. Clin Infect Dis 26:132–137 [CrossRef]
    [Google Scholar]
  12. Haupt Y., Maya R., Kazaz A., Oren M. 1997; Mdm2 promotes the rapid degradation of p53. Nature 387:296–299 [CrossRef]
    [Google Scholar]
  13. Hobbs W. E., DeLuca N. A. 1999; Perturbation of cell cycle progression and cellular gene expression as a function of herpes simplex virus ICP0. J Virol 73:8245–8255
    [Google Scholar]
  14. Kashanchi F., Araujo J., Doniger J., Muralidhar S., Hoch R., Khleif S., Mendelson E., Thompson J., Azumi N. other authors 1997; Human herpesvirus 6 (HHV-6) ORF-1 transactivating gene exhibits malignant transforming activity and its protein binds to p53. Oncogene 14:359–367 [CrossRef]
    [Google Scholar]
  15. Komarov P. G., Komarova E. A., Kondratov R. V., Christov-Tselkov K., Coon J. S., Chernov M. V., Gudkov A. V. 1999; A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. Science 285:1733–1737 [CrossRef]
    [Google Scholar]
  16. Kubbutat M. H., Jones S. N., Vousden K. H. 1997; Regulation of p53 stability by Mdm2. Nature 387:299–303 [CrossRef]
    [Google Scholar]
  17. Martin M. E., Berk A. J. 1998; Adenovirus E1B 55K represses p53 activation in vitro. J Virol 72:3146–3154
    [Google Scholar]
  18. Mocarski E. S. Jr 2002; Immunomodulation by cytomegaloviruses: manipulative strategies beyond evasion. Trends Microbiol 10:332–339 [CrossRef]
    [Google Scholar]
  19. Øster B., Höllsberg P. 2002; Viral gene expression patterns in human herpesvirus 6B-infected T cells. J Virol 76:7578–7586 [CrossRef]
    [Google Scholar]
  20. Øster B., Bundgaard B., Höllsberg P. 2005; Human herpesvirus 6B induces cell cycle arrest concomitant with p53 phosphorylation and accumulation in T cells. J Virol 79:1961–1965 [CrossRef]
    [Google Scholar]
  21. Øster B., Kaspersen M. D., Kofod-Olsen E., Bundgaard B., Höllsberg P. 2006; Human herpesvirus 6B inhibits cell proliferation by a p53-independent pathway. J Clin Virol 37:S63–S68 [CrossRef]
    [Google Scholar]
  22. Pedersen S. M., Höllsberg P. 2006; Complexities in human herpesvirus-6A and -6B binding to host cells. Virology 356:1–3 [CrossRef]
    [Google Scholar]
  23. Pedersen S. M., Øster B., Bundgaard B., Höllsberg P. 2006; Induction of cell–cell fusion from without by human herpesvirus 6B. J Virol 80:9916–9920 [CrossRef]
    [Google Scholar]
  24. Shin Y. C., Nakamura H., Liang X., Feng P., Chang H., Kowalik T. F., Jung J. U. 2006; Inhibition of the ATM/p53 signal transduction pathway by Kaposi's sarcoma-associated herpesvirus interferon regulatory factor 1. J Virol 80:2257–2266 [CrossRef]
    [Google Scholar]
  25. Takaoka A., Hayakawa S., Yanai H., Stoiber D., Negishi H., Kikuchi H., Sasaki S., Imai K., Shibue T. other authors 2003; Integration of interferon- α / β signalling to p53 responses in tumour suppression and antiviral defence. Nature 424:516–523 [CrossRef]
    [Google Scholar]
  26. Takemoto M., Mori Y., Ueda K., Kondo K., Yamanishi K. 2004; Productive human herpesvirus 6 infection causes aberrant accumulation of p53 and prevents apoptosis. J Gen Virol 85:869–879 [CrossRef]
    [Google Scholar]
  27. Takemoto M., Koike M., Mori Y., Yonemoto S., Sasamoto Y., Kondo K., Uchiyama Y., Yamanishi K. 2005; Human herpesvirus 6 open reading frame U14 protein and cellular p53 interact with each other and are contained in the virion. J Virol 79:13037–13046 [CrossRef]
    [Google Scholar]
  28. Vogelstein B., Lane D., Levine A. J. 2000; Surfing the p53 network. Nature 408:307–310 [CrossRef]
    [Google Scholar]
  29. Wang X. W., Forrester K., Yeh H., Feitelson M. A., Gu J. R., Harris C. C. 1994; Hepatitis B virus X protein inhibits p53 sequence-specific DNA binding, transcriptional activity, and association with transcription factor ERCC3. Proc Natl Acad Sci U S A 91:2230–2234 [CrossRef]
    [Google Scholar]
  30. Wei C. L., Wu Q., Vega V. B., Chiu K. P., Ng P., Zhang T., Shahab A., Yong H. C., Fu Y. other authors 2006; A global map of p53 transcription-factor binding sites in the human genome. Cell 124:207–219 [CrossRef]
    [Google Scholar]
  31. Wing B. A., Johnson R. A., Huang E. S. 1998; Identification of positive and negative regulatory regions involved in regulating expression of the human cytomegalovirus UL94 late promoter: role of IE2-86 and cellular p53 in mediating negative regulatory function. J Virol 72:1814–1825
    [Google Scholar]
  32. Yamanishi K., Okuno T., Shiraki K., Takahashi M., Kondo T., Asano Y., Kurata T. 1988; Identification of human herpesvirus-6 as a causal agent for exanthem subitum. Lancet 1:1065–1067
    [Google Scholar]
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