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
2019-11-21
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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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