1887

Abstract

studies have established that the latency-associated nuclear antigen encoded by human Kaposi's sarcoma-associated herpesvirus and the related ORF73 gene product of herpesvirus saimiri interact with virus origins of replication to facilitate maintenance of episomal DNA. Such a function implies a critical role for ORF73 in the establishment and maintenance of latency . To determine the role of ORF73 in virus pathogenesis, the ORF73 gene product encoded by murine herpesvirus-68 (MHV-68) was disrupted by making an ORF73 deletion mutant, Δ73, and an independent ORF73 frameshift mutant, FS73. The effect of the mutations introduced in ORF73 on MHV-68 pathogenesis was analysed using a well-characterized murine model system. These studies have revealed that ORF73 is not required for efficient lytic replication either or . In contrast, a severe latency deficit is observed in splenocytes of animals infected with an ORF73 mutant, as assessed by infectious centre reactivation assay or by hybridization detection of latent virus. Assessment of viral genome-positive cells in sorted splenocyte populations confirmed the absence of ORF73 mutant virus from splenic latency reservoirs, including germinal centre B cells. These data indicate a crucial role for ORF73 in the establishment of latency and for virus persistence in the host.

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2003-12-01
2024-03-29
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References

  1. Adler H., Messerle M., Wagner M., Koszinowski U. H. 2000; Cloning and mutagenesis of the murine gammaherpesvirus 68 genome as an infectious bacterial artificial chromosome. J Virol 74:6964–6974
    [Google Scholar]
  2. Adler H., Messerle M., Koszinowski U. H. 2001; Virus reconstituted from infectious bacterial artificial chromosome (BAC)-cloned murine gammaherpesvirus 68 acquires wild-type properties in vivo only after excision of BAC vector sequences. J Virol 75:5692–5696
    [Google Scholar]
  3. Arthur J., Efstathiou S., Simmons A. 1993; Intranuclear foci containing low abundance herpes simplex virus latency-associated transcripts visualized by non-isotopic in situ hybridization. J Gen Virol 74:1363–1370
    [Google Scholar]
  4. 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
    [Google Scholar]
  5. 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
    [Google Scholar]
  6. Blasdell K., McCracken C., Morris A., Nash A. A., Begon M., Bennett M., Stewart J. P. 2003; The wood mouse is a natural host for Murid herpesvirus 4 . J Gen Virol 84:111–113
    [Google Scholar]
  7. Blaskovic D., Stancekova M., Svobodova J., Mistrikova J. 1980; Isolation of five strains of herpesviruses from two species of free living small rodents. Acta Virol 24:468
    [Google Scholar]
  8. Bonnefoix T., Bonnefoix P., Callanan M., Verdiel P., Sotto J. J. 2001; Graphical representation of a generalized linear model-based statistical test estimating the fit of the single-hit Poisson model to limiting dilution assays. J Immunol 167:5725–5730
    [Google Scholar]
  9. Bowden R. J., Simas J. P., Davis A. J., Efstathiou S. 1997; Murine gammaherpesvirus 68 encodes tRNA-like sequences which are expressed during latency. J Gen Virol 78:1675–1687
    [Google Scholar]
  10. Bridgeman A., Stevenson P. G., Simas J. P., Efstathiou S. 2001; A secreted chemokine binding protein encoded by murine gammaherpesvirus-68 is necessary for the establishment of a normal viral load. J Exp Med 194:301–312
    [Google Scholar]
  11. 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]
  12. 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]
  13. Cotter M. A. II, Robertson E. S. 1999; The latency-associated nuclear antigen tethers Kaposi's sarcoma-associated herpesvirus genome to host chromosomes in body cavity-based lymphoma cells. Virology 264:254–264
    [Google Scholar]
  14. Doherty P. C., Christensen J. P., Belz G. T., Stevenson P. G., Sangster M. Y. 2001; Dissecting the host response to a gamma-herpesvirus. Philos Trans R Soc Lond B Biol Sci 356:581–593
    [Google Scholar]
  15. Efstathiou S., Ho Y. M., Minson A. C. 1990; Cloning and molecular characterization of the murine herpesvirus 68 genome. J Gen Virol 71:1355–1364
    [Google Scholar]
  16. Flano E., Husain S. M., Sample J. T., Woodland D. L., Blackman M. A. 2000; Latent murine gamma-herpesvirus infection is established in activated B cells, dendritic cells, and macrophages. J Immunol 165:1074–1081
    [Google Scholar]
  17. Flano E., Woodland D. L., Blackman M. A. 2002a; A mouse model for infectious mononucleosis. Immunol Res 25:201–217
    [Google Scholar]
  18. Flano E., Kim I.-J., Woodland D. L., Blackman M. A. 2002b; Gamma-herpesvirus latency is preferentially maintained in splenic germinal centre and memory B cells. J Exp Med 196:1363–1372
    [Google Scholar]
  19. Flano E., Kim I.-J., Moore J., Woodland D. L., Blackman M. A. 2003; Differential gamma-herpesvirus distribution in distinct anatomical locations and cell subsets during persistent infection in mice. J Immunol 70:3828–3834
    [Google Scholar]
  20. Friborg J. Jr, Kong W.-P., Hottiger M. O., Nabel G. J. 1999; p53 inhibition by the LANA protein of KSHV protects against cell death. Nature 402:889–894
    [Google Scholar]
  21. Garber A. C., Shu M. A., Hu J., Renne R. 2001; DNA binding and modulation of gene expression by the latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus. J Virol 75:7882–7892
    [Google Scholar]
  22. Garber A. C., Hu J., Renne R. 2002; Latency-associated nuclear antigen (LANA) cooperatively binds to two sites within the terminal repeat, and both sites contribute to the ability of LANA to suppress transcription and to facilitate DNA replication. J Biol Chem 277:27401–27411
    [Google Scholar]
  23. Gardella T., Medveczky P., Sairenji T., Mulder C. 1984; Detection of circular and linear herpesvirus DNA molecules in mammalian cells by gel electrophoresis. J Virol 50:248–254
    [Google Scholar]
  24. Grundhoff A., Ganem D. 2003; The latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus permits replication of terminal repeat-containing plasmids. J Virol 77:2779–2783
    [Google Scholar]
  25. 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
    [Google Scholar]
  26. Lee M.-A., Diamond M. E., Yates J. L. 1999; Genetic evidence that EBNA-1 is needed for efficient, stable latent infection by Epstein–Barr virus. J Virol 73:2974–2982
    [Google Scholar]
  27. Lee B. J., Koszinowski U. H., Sarawar S. R., Adler H. 2003; A gammaherpesvirus G protein-coupled receptor homologue is required for increased viral replication in response to chemokines and efficient reactivation from latency. J Immunol 170:243–251
    [Google Scholar]
  28. Lupton S., Levine A. J. 1985; Mapping genetic elements of Epstein–Barr virus that facilitate extrachromosomal persistence of Epstein–Barr virus-derived plasmids in human cells. Mol Cell Biol 5:2533–2542
    [Google Scholar]
  29. Marques S., Efstathiou S., Smith K. G., Haury M., Simas J. P. 2003; Selective gene expression of latent murine gammaherpesvirus 68 in B lymphocytes. J Virol 77:7308–7318
    [Google Scholar]
  30. Mattsson K., Kiss C., Platt G. M., Simpson G. R., Kashuba E., Klein G., Schulz T. F., Szekely L. 2002; Latent nuclear antigen of Kaposi's sarcoma herpesvirus/human herpesvirus-8 induces and relocates RING3 to nuclear heterochromatin regions. J Gen Virol 83:179–188
    [Google Scholar]
  31. Messerle M., Crnkovic I., Hammerschmidt W., Ziegler H., Koszinowski U. H. 1997; Cloning and mutagenesis of a herpesvirus genome as an infectious bacterial artificial chromosome. Proc Natl Acad Sci U S A 94:14759–14763
    [Google Scholar]
  32. Nash A. A., Dutia B. M., Stewart J. P., Davison A. J. 2001; Natural history of murine gamma-herpesvirus infection. Philos Trans R Soc Lond B Biol Sci 356:569–579
    [Google Scholar]
  33. Radkov S. A., Kellam P., Boshoff C. 2000; The latent nuclear antigen of Kaposi sarcoma-associated herpesvirus targets the retinoblastoma-E2F pathway and with the oncogene Hras transforms primary rat cells. Nat Med 6:1121–1127
    [Google Scholar]
  34. Reisman D., Yates J., Sugden B. 1985; A putative origin of replication of plasmids derived from Epstein–Barr virus is composed of two cis -acting components. Mol Cell Biol 5:1822–1832
    [Google Scholar]
  35. Renne R., Barry C., Dittmer D., Compitello N., Brown P. O., Ganem D. 2001; Modulation of cellular and viral gene expression by the latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus. J Virol 75:458–468
    [Google Scholar]
  36. Schwam D. R., Luciano R. L., Mahajan S. S., Wong L., Wilson A. C. 2000; Carboxy terminus of human herpesvirus 8 latency-associated nuclear antigen mediates dimerization, transcriptional repression, and targeting to nuclear bodies. J Virol 74:8532–8540
    [Google Scholar]
  37. Simas J. P., Efstathiou E. 1998; Murine gammherpesvirus 68: a model for the study of gammaherpesvirus pathogenesis. Trends Microbiol 6:276–282
    [Google Scholar]
  38. Simas J. P., Bowden R. J., Paige V., Efstathiou S. 1998; Four tRNA-like sequences and a serpin homologue encoded by murine gammaherpesvirus 68 are dispensable for lytic replication in vitro and latency in vivo . J Gen Virol 79:149–153
    [Google Scholar]
  39. Simas J. P., Swann D., Bowden R., Efstathiou S. 1999; Analysis of murine gammaherpesvirus-68 transcription during lytic and latent infection. J Gen Virol 80:75–82
    [Google Scholar]
  40. 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
    [Google Scholar]
  41. Stevenson P. G., May J. S., Smith X. G., Marques S., Adler H., Koszinowski U. H., Simas J. P., Efstathiou S. 2002; K3-mediated evasion of CD8+ T cells aids amplification of a latent γ -herpesvirus. Nat Immunol 3:733–740
    [Google Scholar]
  42. Stewart J. P., Usherwood E. J., Ross A., Dyson H., Nash A. A. 1998; Lung epithelial cells are a major site of murine gammaherpesvirus persistence. J Exp Med 187:1941–1951
    [Google Scholar]
  43. Sunil-Chandra N. P., Efstathiou S., Nash A. A. 1992; Murine gammaherpesvirus 68 establishes a latent infection in mouse B lymphocytes in vivo . J Gen Virol 73:3275–3279
    [Google Scholar]
  44. Sunil-Chandra N. P., Efstathiou S., Nash A. A. 1993; Interactions of murine gammaherpesvirus 68 with B and T cell lines. Virology 193:825–833
    [Google Scholar]
  45. van Dyk L. F., Virgin H. W. IV, Speck S. H. 2000; The murine gammaherpesvirus 68 v-cyclin is a critical regulator of reactivation from latency. J Virol 74:7451–7461
    [Google Scholar]
  46. van Dyk L. F., Virgin H. W. IV, Speck S. H. 2003; Maintenance of gammaherpesvirus latency requires viral cyclin in the absence of B lymphocytes. J Virol 77:5118–5126
    [Google Scholar]
  47. Viejo-Borbolla A., Kati E., Sheldon J. A., Nathan K., Mattsson K., Szekely L., Schulz T. F. 2003; A domain in the C-terminal region of latency-associated nuclear antigen 1 of Kaposi's sarcoma-associated herpesvirus affects transcriptional activation and binding to nuclear heterochromatin. J Virol 77:7093–7100
    [Google Scholar]
  48. Virgin H. W. IV, Latreille P., Wamsley P., Hallsworth K., Weck K. E., Dal Canto A. J., Speck S. H. 1997; Complete sequence and genomic analysis of murine gammaherpesvirus 68. J Virol 71:5894–5904
    [Google Scholar]
  49. Weck K. E., Barkon M. L., Yoo L. I., Speck S. H., Virgin H. W. IV 1996; Mature B cells are required for acute splenic infection, but not for establishment of latency, by murine gammaherpesvirus 68. J Virol 70:6775–6780
    [Google Scholar]
  50. Weck K. E., Kim S. S., Virgin H. W. IV, Speck S. H. 1999; B cells regulate murine gammaherpesvirus 68 latency. J Virol 73:4651–4661
    [Google Scholar]
  51. Willer D. O., Speck S. H. 2003; Long-term latent murine gammaherpesvirus 68 infection is preferentially found within the surface immunoglobulin D-negative subset of splenic B cells in vivo . J Virol 77:8310–8321
    [Google Scholar]
  52. Yates J. L., Warren N., Reisman D., Sugden B. 1984; A cis -acting element from the Epstein–Barr viral genome that permits stable replication of recombinant plasmids in latently infected cells. Proc Natl Acad Sci U S A 81:3806–3810
    [Google Scholar]
  53. Yates J. L., Warren N., Sugden B. 1985; Stable replication of plasmids derived from Epstein–Barr virus in various mammalian cells. Nature 313:812–815
    [Google Scholar]
  54. Yates J. L., Camiolo S. M., Bashaw J. M. 2000; The minimal replicator of Epstein–Barr virus oriP. J Virol 74:4512–4522
    [Google Scholar]
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