1887

Abstract

Herpesvirus saimiri (HVS) establishes a persistent infection in which the viral genome persists as a circular non-integrated episome. ORF73 tethers HVS episomes to host mitotic chromosomes, allowing episomal persistence via an interaction with the chromosome-associated protein, MeCP2. Here we demonstrate that ORF73 also interacts with the linker histone H1 via its C terminus, suggesting it associates with multiple chromosome-associated proteins. In addition, we show that the C terminus is also required for the ability of ORF73 to bind the terminal repeat region of the HVS genome. These results suggest that the ORF73 C terminus contains all the necessary elements required for HVS episomal persistence. Using a range of ORF73 C terminus deletions to rescue the episomal maintenance properties of a HVSΔ73 recombinant virus, we show that a C terminus region comprising residues 285–407 is sufficient to maintain the HVS episome in a dividing cell population.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.2008/002725-0
2008-11-01
2019-11-18
Loading full text...

Full text loading...

/deliver/fulltext/jgv/89/11/2843.html?itemId=/content/journal/jgv/10.1099/vir.0.2008/002725-0&mimeType=html&fmt=ahah

References

  1. Adkins, N. L., Watts, M. & Georgel, P. T. ( 2004; ). To the 30-nm chromatin fiber and beyond. Biochim Biophys Acta 1677, 12–23.[CrossRef]
    [Google Scholar]
  2. Ballestas, M. E. & Kaye, K. M. ( 2001; ). Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen 1 mediates episome persistence through cis-acting terminal repeat (TR) sequence and specifically binds TR DNA. J Virol 75, 3250–3258.[CrossRef]
    [Google Scholar]
  3. Ballestas, M. E., Chatis, P. A. & Kaye, K. M. ( 1999; ). Efficient persistence of extrachromosomal KSHV DNA mediated by latency-associated nuclear antigen. Science 284, 641–644.[CrossRef]
    [Google Scholar]
  4. Barbera, A. J., Chodaparambil, J. V., Kelley-Clarke, B., Joukov, V., Walter, J. C., Luger, K. & Kaye, K. M. ( 2006; ). The nucleosomal surface as a docking station for Kaposi's sarcoma herpesvirus LANA. Science 311, 856–861.[CrossRef]
    [Google Scholar]
  5. Biesinger, B., Muller-Fleckenstein, I., Simmer, B., Lang, G., Wittmann, S., Platzer, E., Desrosiers, R. C. & Fleckenstein, B. ( 1992; ). Stable growth transformation of human T lymphocytes by herpesvirus saimiri. Proc Natl Acad Sci U S A 89, 3116–3119.[CrossRef]
    [Google Scholar]
  6. Calderwood, M. A., Hall, K. T., Matthews, D. A. & Whitehouse, A. ( 2004a; ). The herpesvirus saimiri ORF73 gene product interacts with host-cell mitotic chromosomes and self-associates via its C terminus. J Gen Virol 85, 147–153.[CrossRef]
    [Google Scholar]
  7. Calderwood, M. A., White, R. E. & Whitehouse, A. ( 2004b; ). Development of herpesvirus-based episomally maintained gene delivery vectors. Expert Opin Biol Ther 4, 493–505.[CrossRef]
    [Google Scholar]
  8. Calderwood, M., White, R. E., Griffiths, R. A. & Whitehouse, A. ( 2005; ). Open reading frame 73 is required for herpesvirus saimiri A11-S4 episomal persistence. J Gen Virol 86, 2703–2708.[CrossRef]
    [Google Scholar]
  9. Collins, C. M. & Medveczky, P. G. ( 2002; ). Genetic requirements for the episomal maintenance of oncogenic herpesvirus genomes. Adv Cancer Res 84, 155–174.
    [Google Scholar]
  10. Collins, C. M., Medveczky, M. M., Lund, T. & Medveczky, P. G. ( 2002; ). The terminal repeats and latency-associated nuclear antigen of herpesvirus saimiri are essential for episomal persistence of the viral genome. J Gen Virol 83, 2269–2278.
    [Google Scholar]
  11. Cotter, M. A., II & Robertson, E. S. ( 1999; ). The latency-associated nuclear antigen tethers the Kaposi's sarcoma-associated herpesvirus genome to host chromosomes in body cavity-based lymphoma cells. Virology 264, 254–264.[CrossRef]
    [Google Scholar]
  12. Cotter, M. A., Subramanian, C. & Robertson, E. S. ( 2001; ). The Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen binds to specific sequences at the left end of the viral genome through its carboxy-terminus. Virology 291, 241–259.[CrossRef]
    [Google Scholar]
  13. Fickenscher, H. & Fleckenstein, B. ( 2001; ). Herpesvirus saimiri. Philos Trans R Soc Lond B Biol Sci 356, 545–567.[CrossRef]
    [Google Scholar]
  14. Griffiths, R. & Whitehouse, A. ( 2007; ). Herpesvirus saimiri episomal persistence is maintained via interaction between open reading frame 73 and the cellular chromosome-associated protein MeCP2. J Virol 81, 4021–4032.[CrossRef]
    [Google Scholar]
  15. Griffiths, R. A., Boyne, J. R. & Whitehouse, A. ( 2006; ). Herpesvirus saimiri-based gene delivery vectors. Curr Gene Ther 6, 1–15.
    [Google Scholar]
  16. Hall, K. T., Giles, M. S., Goodwin, D. J., Calderwood, M. A., Carr, I. M., Stevenson, A. J., Markham, A. F. & Whitehouse, A. ( 2000a; ). Analysis of gene expression in a human cell line stably transduced with herpesvirus saimiri. J Virol 74, 7331–7337.[CrossRef]
    [Google Scholar]
  17. Hall, K. T., Giles, M. S., Goodwin, D. J., Calderwood, M. A., Markham, A. F. & Whitehouse, A. ( 2000b; ). Characterization of the herpesvirus saimiri ORF73 gene product. J Gen Virol 81, 2653–2658.
    [Google Scholar]
  18. Kaschka-Dierich, C., Werner, F. J., Bauer, I. & Fleckenstein, B. ( 1982; ). Structure of nonintegrated, circular herpesvirus saimiri and herpesvirus ateles genomes in tumor cell lines and in vitro-transformed cells. J Virol 44, 295–310.
    [Google Scholar]
  19. Krithivas, A., Fujimuro, M., Weidner, M., Young, D. B. & Hayward, S. D. ( 2002; ). Protein interactions targeting the latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus to cell chromosomes. J Virol 76, 11596–11604.[CrossRef]
    [Google Scholar]
  20. Macnab, S., White, R., Hiscox, J. & Whitehouse, A. ( 2008; ). Production of an infectious Herpesvirus saimiri-based episomally maintained amplicon system. J Biotechnol 134, 287–296.[CrossRef]
    [Google Scholar]
  21. Shinohara, H., Fukushi, M., Higuchi, M., Oie, M., Hoshi, O., Ushiki, T., Hayashi, J.-I. & Fujii, M. ( 2002; ). Chromosome binding site of latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus is essential for persistent episome maintenance and is functionally replaced by histone H1. J Virol 76, 12917–12924.[CrossRef]
    [Google Scholar]
  22. Smith, P. G., Coletta, P. L., Markham, A. F. & Whitehouse, A. ( 2001; ). In vivo episomal maintenance of a herpesvirus saimiri-based gene delivery vector. Gene Ther 8, 1762–1769.[CrossRef]
    [Google Scholar]
  23. Verma, S. C. & Robertson, E. S. ( 2003; ). ORF73 of herpesvirus saimiri strain C488 tethers the viral genome to metaphase chromosomes and binds to cis-acting DNA sequences in the terminal repeats. J Virol 77, 12494–12506.[CrossRef]
    [Google Scholar]
  24. Viejo-Borbolla, A., Ottinger, M., Bruning, E., Burger, A., Konig, R., Kati, E., Sheldon, J. A. & Schulz, T. F. ( 2005; ). Brd2/RING3 interacts with a chromatin-binding domain in the Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen 1 (LANA-1) that is required for multiple functions of LANA-1. J Virol 79, 13618–13629.[CrossRef]
    [Google Scholar]
  25. Werner, F.-J., Bornkamm, G. W. & Fleckenstein, B. ( 1977; ). Episomal viral DNA in a herpesvirus saimiri-transformed lymphoid cell line. J Virol 22, 794–803.
    [Google Scholar]
  26. White, R. E., Calderwood, M. A. & Whitehouse, A. ( 2003; ). Generation and precise modification of a herpesvirus saimiri bacterial artificial chromosome demonstrates that the terminal repeats are required for both virus production and episomal persistence. J Gen Virol 84, 3393–3403.[CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.2008/002725-0
Loading
/content/journal/jgv/10.1099/vir.0.2008/002725-0
Loading

Data & Media loading...

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