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PMID: 10906198 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

The murine gammaherpesvirus 68 v-cyclin is a critical regulator of reactivation from latency.

Journal of virology ·Vol. 74 ·No. 16 ·2000-08-00 ·Pages 7451-61

van Dyk LF, Virgin HW, Speck SH

Abstract

Gamma-2 herpesviruses encode a homolog of mammalian D-type cyclins. The v-cyclin encoded by murine gammaherpesvirus 68 (gammaHV68) induces cell cycle progression and is an oncogene (L. F. van Dyk, J. L. Hess, J. D. Katz, M. Jacoby, S. H. Speck, and H. W. Virgin IV, J. Virol. 73:5110-5122, 1999). However, the role of the pro-proliferative v-cyclins in gamma-2 herpesvirus pathogenesis is not known. Here we report the generation and characterization of a gammaHV68 v-cyclin mutant (v-cyclin.LacZ) that is unable to express a functional v-cyclin protein. Notably, although the gammaHV68 v-cyclin is expressed from an early-late lytic transcript, v-cyclin. LacZ replicated normally in fibroblasts in vitro and during acute infection in the spleen, liver, and lungs in vivo. Moreover, v-cyclin.LacZ exhibited wild-type (wt) virulence in mice with severe combined immunodeficiency. In addition, in a model of gammaHV68-induced chronic disease in mice lacking the gamma interferon receptor (IFNgammaR(-/-)), v-cyclin.LacZ virus was similar to wt gammaHV68 in terms of the incidence of mortality and vasculitis. Further analysis revealed that the frequencies of splenocytes and peritoneal cells harboring the latent gammaHV68 genome in normal and B-cell-deficient mice infected with wt gammaHV68 or v-cyclin.LacZ were very similar. However, v-cyclin.LacZ was significantly compromised in its capacity to reactivate from latency. This phenotype was conclusively mapped to the v-cyclin gene by (i) generating a marker rescue virus (v-cyclin.MR) from the v-cyclin.LacZ mutant, which restored the frequency of cells in which virus reactivated from latency to the levels observed with wt gammaHV68; and (ii) generating a second v-cyclin mutant virus containing a translation stop codon within the v-cyclin gene (v-cyclin.stop), which was compromised in reactivation from latency. These studies demonstrate that despite expression as a lytic cycle gene, the pro-proliferative gammaHV68 v-cyclin is not required for gammaHV68 replication either in vitro or during acute infection in vivo but rather is a critical determinant of reactivation from latency.

MeSH Terms
Animals Cells, Cultured Cyclins/genetics,physiology Fibroblasts Gammaherpesvirinae/genetics,pathogenicity,physiology Gene Expression Regulation, Viral Gene Targeting Herpesviridae Infections/virology Interferon-gamma/deficiency,physiology Mice Mice, SCID Viral Proteins Virulence Virus Activation Virus Latency Virus Replication
Chemicals
Cyclins Viral Proteins Interferon-gamma
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
van Dyk L F
Department of Pathology and Immunology and Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA.
Virgin H W
Speck S H
References (70)
70 references, click to expand
  1. Virus-encoded cyclin.
    Mol Cell Biol. 1994 Nov;14(11):7235-44 PMID: 7935438
  2. Interactions of the murine gammaherpesvirus with the immune system.
    Curr Opin Immunol. 1994 Aug;6(4):560-3 PMID: 7946042
  3. Expression of cyclin D2 in Epstein-Barr virus-positive Burkitt's lymphoma cell lines is related to methylation status of the gene.
    J Virol. 1995 Feb;69(2):1292-5 PMID: 7529333
  4. The complement control protein homolog of herpesvirus saimiri regulates serum complement by inhibiting C3 convertase activity.
    J Virol. 1995 Jun;69(6):3889-92 PMID: 7745740
  5. Murine herpesvirus 68 is genetically related to the gammaherpesviruses Epstein-Barr virus and herpesvirus saimiri.
    J Gen Virol. 1990 Jun;71 ( Pt 6):1365-72 PMID: 2161903
  6. A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene.
    Nature. 1991 Apr 4;350(6317):423-6 PMID: 1901381
  7. Mechanism of CDK activation revealed by the structure of a cyclinA-CDK2 complex.
    Nature. 1995 Jul 27;376(6538):313-20 PMID: 7630397
  8. Latent membrane protein-1 induces cyclin D2 expression, pRb hyperphosphorylation, and loss of TGF-beta 1-mediated growth inhibition in EBV-positive B cells.
    J Immunol. 1995 Aug 1;155(3):1047-56 PMID: 7636179
  9. The normal cell cycle activation program is exploited during the infection of quiescent B lymphocytes by Epstein-Barr virus.
    Cancer Res. 1995 Nov 1;55(21):4784-7 PMID: 7585505
  10. The latency-related gene of bovine herpesvirus 1 encodes a product which inhibits cell cycle progression.
    J Virol. 1996 Jun;70(6):3807-14 PMID: 8648716
  11. The Epstein-Barr virus bZIP transcription factor Zta causes G0/G1 cell cycle arrest through induction of cyclin-dependent kinase inhibitors.
    EMBO J. 1996 Jun 3;15(11):2748-59 PMID: 8654372
  12. Cyclin encoded by KS herpesvirus.
    Nature. 1996 Aug 1;382(6590):410 PMID: 8684480
  13. Expression of human herpesvirus 8-encoded cyclin D in Kaposi's sarcoma spindle cells.
    J Natl Cancer Inst. 1997 Dec 17;89(24):1868-74 PMID: 9414174
  14. Effector CD4+ and CD8+ T-cell mechanisms in the control of respiratory virus infections.
    Immunol Rev. 1997 Oct;159:105-17 PMID: 9416506
  15. Transcription mapping of the Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) genome in a body cavity-based lymphoma cell line (BC-1).
    J Virol. 1998 Feb;72(2):1005-12 PMID: 9444993
  16. Cell cycle dysregulation by human cytomegalovirus: influence of the cell cycle phase at the time of infection and effects on cyclin transcription.
    J Virol. 1998 May;72(5):3729-41 PMID: 9557655
  17. Requirement for cellular cyclin-dependent kinases in herpes simplex virus replication and transcription.
    J Virol. 1998 Jul;72(7):5626-37 PMID: 9621021
  18. A cluster of latently expressed genes in Kaposi's sarcoma-associated herpesvirus.
    J Virol. 1998 Oct;72(10):8309-15 PMID: 9733875
  19. Characterization and cell cycle regulation of the major Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) latent genes and their promoter.
    J Virol. 1999 Feb;73(2):1438-46 PMID: 9882349
  20. Degradation of p27(Kip) cdk inhibitor triggered by Kaposi's sarcoma virus cyclin-cdk6 complex.
    EMBO J. 1999 Feb 1;18(3):644-53 PMID: 9927424
  21. Modulation of p27(Kip1) levels by the cyclin encoded by Kaposi's sarcoma-associated herpesvirus.
    EMBO J. 1999 Feb 1;18(3):654-63 PMID: 9927425
  22. Analysis of murine gammaherpesvirus-68 transcription during lytic and latent infection.
    J Gen Virol. 1999 Jan;80 ( Pt 1):75-82 PMID: 9934687
  23. Three distinct regions of the murine gammaherpesvirus 68 genome are transcriptionally active in latently infected mice.
    J Virol. 1999 Mar;73(3):2321-32 PMID: 9971815
  24. Induced expression of p16(INK4a) inhibits both CDK4- and CDK2-associated kinase activity by reassortment of cyclin-CDK-inhibitor complexes.
    Mol Cell Biol. 1999 Mar;19(3):1981-9 PMID: 10022885
  25. Macrophages are the major reservoir of latent murine gammaherpesvirus 68 in peritoneal cells.
    J Virol. 1999 Apr;73(4):3273-83 PMID: 10074181
  26. Crystal structure of a viral cyclin, a positive regulator of cyclin-dependent kinase 6.
    Structure. 1999 Mar 15;7(3):245-54 PMID: 10368294
  27. B cells regulate murine gammaherpesvirus 68 latency.
    J Virol. 1999 Jun;73(6):4651-61 PMID: 10233924
  28. The murine gammaherpesvirus 68 v-cyclin gene is an oncogene that promotes cell cycle progression in primary lymphocytes.
    J Virol. 1999 Jun;73(6):5110-22 PMID: 10233974
  29. Viral encoded cyclins.
    Semin Cancer Biol. 1999 Jun;9(3):221-9 PMID: 10343073
  30. Murine gammaherpesvirus M2 gene is latency-associated and its protein a target for CD8(+) T lymphocytes.
    Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7508-13 PMID: 10377445
  31. CDK inhibitors: positive and negative regulators of G1-phase progression.
    Genes Dev. 1999 Jun 15;13(12):1501-12 PMID: 10385618
  32. Murine gammaherpesvirus 68 encodes a functional regulator of complement activation.
    J Virol. 1999 Sep;73(9):7658-70 PMID: 10438856
  33. Unraveling immunity to gamma-herpesviruses: a new model for understanding the role of immunity in chronic virus infection.
    Curr Opin Immunol. 1999 Aug;11(4):371-9 PMID: 10448140
  34. Host and viral genetics of chronic infection: a mouse model of gamma-herpesvirus pathogenesis.
    Curr Opin Microbiol. 1999 Aug;2(4):403-9 PMID: 10458986
  35. Expression of cell-homologous genes of human herpesvirus-8 in human immunodeficiency virus-negative lymphoproliferative diseases.
    Blood. 1999 Oct 15;94(8):2931-3 PMID: 10515899
  36. Identification of the gene encoding the major latency-associated nuclear antigen of the Kaposi's sarcoma-associated herpesvirus.
    J Clin Invest. 1997 Nov 15;100(10):2606-10 PMID: 9366576
  37. Kaposi's sarcoma-associated herpesvirus-encoded v-cyclin triggers apoptosis in cells with high levels of cyclin-dependent kinase 6.
    Cancer Res. 1999 Oct 1;59(19):4984-9 PMID: 10519412
  38. Structural basis of cyclin-dependent kinase activation by phosphorylation.
    Nat Struct Biol. 1996 Aug;3(8):696-700 PMID: 8756328
  39. Mature B cells are required for acute splenic infection, but not for establishment of latency, by murine gammaherpesvirus 68.
    J Virol. 1996 Oct;70(10):6775-80 PMID: 8794315
  40. Human cytomegalovirus inhibits cellular DNA synthesis and arrests productively infected cells in late G1.
    Virology. 1996 Oct 1;224(1):150-60 PMID: 8862409
  41. Epstein-Barr virus exploits the normal cell pathway to regulate Rb activity during the immortalisation of primary B-cells.
    Oncogene. 1996 Oct 3;13(7):1413-21 PMID: 8875979
  42. Kaposi's sarcoma-associated herpesvirus contains G protein-coupled receptor and cyclin D homologs which are expressed in Kaposi's sarcoma and malignant lymphoma.
    J Virol. 1996 Nov;70(11):8218-23 PMID: 8892957
  43. The dynamics of cyclin dependent kinase structure.
    Curr Opin Cell Biol. 1996 Dec;8(6):767-72 PMID: 8939669
  44. Nucleotide sequence of the Kaposi sarcoma-associated herpesvirus (HHV8).
    Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14862-7 PMID: 8962146
  45. Human cytomegalovirus infection inhibits G1/S transition.
    J Virol. 1997 Feb;71(2):1629-34 PMID: 8995690
  46. The cyclin box and C-terminus of cyclins A and E specify CDK activation and substrate specificity.
    Oncogene. 1997 Jan 30;14(4):491-8 PMID: 9053846
  47. Kaposi's sarcoma-associated herpesvirus encodes a functional cyclin.
    J Virol. 1997 Mar;71(3):1984-91 PMID: 9032330
  48. The cyclin encoded by Kaposi's sarcoma-associated herpesvirus stimulates cdk6 to phosphorylate the retinoblastoma protein and histone H1.
    J Virol. 1997 Jun;71(6):4193-8 PMID: 9151805
  49. Pathological changes in the spleens of gamma interferon receptor-deficient mice infected with murine gammaherpesvirus: a role for CD8 T cells.
    J Virol. 1997 Jun;71(6):4278-83 PMID: 9151815
  50. Complete sequence and genomic analysis of murine gammaherpesvirus 68.
    J Virol. 1997 Aug;71(8):5894-904 PMID: 9223479
  51. The 222- to 234-kilodalton latent nuclear protein (LNA) of Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) is encoded by orf73 and is a component of the latency-associated nuclear antigen.
    J Virol. 1997 Aug;71(8):5915-21 PMID: 9223481
  52. Tuning into immunological dissonance: an experimental model for infectious mononucleosis.
    Curr Opin Immunol. 1997 Aug;9(4):477-83 PMID: 9287187
  53. Herpes simplex virus 1 alpha regulatory protein ICP0 interacts with and stabilizes the cell cycle regulator cyclin D3.
    J Virol. 1997 Oct;71(10):7328-36 PMID: 9311810
  54. Herpes viral cyclin/Cdk6 complexes evade inhibition by CDK inhibitor proteins.
    Nature. 1997 Nov 13;390(6656):184-7 PMID: 9367157
  55. Murine gamma-herpesvirus 68 causes severe large-vessel arteritis in mice lacking interferon-gamma responsiveness: a new model for virus-induced vascular disease.
    Nat Med. 1997 Dec;3(12):1346-53 PMID: 9396604
  56. Disruption of the murine gammaherpesvirus 68 M1 open reading frame leads to enhanced reactivation from latency.
    J Virol. 2000 Feb;74(4):1973-84 PMID: 10644370
  57. Physical and functional domains of the herpes simplex virus transcriptional regulatory protein ICP4.
    J Virol. 1988 Mar;62(3):732-43 PMID: 2828668
  58. Complex transcription of the Epstein-Barr virus BamHI fragment H rightward open reading frame 1 (BHRF1) in latently and lytically infected B lymphocytes.
    Proc Natl Acad Sci U S A. 1988 Jun;85(11):3678-82 PMID: 2836854
  59. The scid mouse mutant.
    Curr Top Microbiol Immunol. 1988;137:197-202 PMID: 3416632
  60. Cloning and molecular characterization of the murine herpesvirus 68 genome.
    J Gen Virol. 1990 Jun;71 ( Pt 6):1355-64 PMID: 2351958
  61. A cellular function can enhance gene expression and plating efficiency of a mutant defective in the gene for ICP0, a transactivating protein of herpes simplex virus type 1.
    J Virol. 1991 Aug;65(8):4078-90 PMID: 1649316
  62. Herpesvirus saimiri encodes homologues of G protein-coupled receptors and cyclins.
    Nature. 1992 Jan 23;355(6358):362-5 PMID: 1309943
  63. New member of the multigene family of complement control proteins in herpesvirus saimiri.
    J Virol. 1992 Jun;66(6):3937-40 PMID: 1316492
  64. Primary structure of the herpesvirus saimiri genome.
    J Virol. 1992 Aug;66(8):5047-58 PMID: 1321287
  65. Identification of the domains in cyclin A required for binding to, and activation of, p34cdc2 and p32cdk2 protein kinase subunits.
    Mol Biol Cell. 1992 Nov;3(11):1279-94 PMID: 1333843
  66. Sequences within the conserved cyclin box of human cyclin A are sufficient for binding to and activation of cdc2 kinase.
    Mol Cell Biol. 1993 Feb;13(2):1194-201 PMID: 8423786
  67. Functional interactions of the retinoblastoma protein with mammalian D-type cyclins.
    Cell. 1993 May 7;73(3):487-97 PMID: 8343202
  68. Physical interaction of the retinoblastoma protein with human D cyclins.
    Cell. 1993 May 7;73(3):499-511 PMID: 8490963
  69. In vivo characterization of site-directed mutations in the promoter of the herpes simplex virus type 1 latency-associated transcripts.
    J Gen Virol. 1993 Sep;74 ( Pt 9):1859-69 PMID: 8397283
  70. Functional role of type I and type II interferons in antiviral defense.
    Science. 1994 Jun 24;264(5167):1918-21 PMID: 8009221
Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
0022-538X
DOI
10.1128/jvi.74.16.7451-7461.2000
Published
2000-08-00
Pages
7451-61
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC112265
Subset
IM
Grants
NCI NIH HHS · R01 CA058524 · United States
NHLBI NIH HHS · R01 HL060090 · United States
NCI NIH HHS · R01 CA043143 · United States
NCI NIH HHS · R01 CA052004 · United States
NIAID NIH HHS · T32 AI007163 · United States
NCI NIH HHS · CA52004 · United States
NCI NIH HHS · CA43143 · United States
NCI NIH HHS · R01 CA074730 · United States
NCI NIH HHS · CA58524 · United States
External Links
PubMed source DOI: 10.1128/jvi.74.16.7451-7461.2000 PMC Full Text View journal details
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