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PMID: 16282467 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Murine gammaherpesvirus 68 infection is associated with lymphoproliferative disease and lymphoma in BALB beta2 microglobulin-deficient mice.

Journal of virology ·Vol. 79 ·No. 23 ·2005-12-00 ·Pages 14668-79

Tarakanova VL, Suarez F, Tibbetts SA, Jacoby MA, Weck KE, Hess JL, Speck SH, Virgin HW

Abstract

Human gammaherpesvirus infections are associated with development of lymphoproliferative disease. Understanding of the mechanisms of gammaherpesvirus lymphomagenesis during chronic infection in a natural host has been limited by the exquisite species specificity of human gammaherpesviruses and the expense of primates. Murine gammaherpesvirus gammaHV68 is genetically and biologically related to human gammaherpesviruses and herpesvirus saimiri and has been reported to be associated with lymphoproliferative disease in mice (N. P. Sunil-Chandra, J. Arno, J. Fazakerley, and A. A. Nash, Am. J. Pathol. 145:818-826, 1994). We report the development of an animal model of gammaHV68 lymphomagenesis in BALB/c beta2 microglobulin-deficient mice (BALB beta2m-/-). GammaHV68 infection induced two lymphoproliferative lesions: B-cell lymphoma and atypical lymphoid hyperplasia (ALH). ALH lesion histology resembled lesions of Epstein-Barr virus-associated posttransplant lymphoproliferative disease and was characterized by the abnormal infiltration of the white pulp with cells expressing the plasma cell marker CD138. Lymphomas observed in gammaHV68-infected animals were B220+/CD3- large-cell lymphomas. GammaHV68-infected cells were common in ALH lesions as measured by in situ hybridization with a probe specific for viral tRNAs (vtRNAs), but they were scarce in gammaHV68-infected spleens with normal histology. Unlike ALH lesions, gammaHV68 vtRNA-positive cells were rare in lymphomas. GammaHV68 infection of BALB beta2m-/- mice results in lymphoproliferation and lymphoma, providing a valuable tool for identifying viral and host genes involved in gammaherpesvirus-associated malignancies. Our findings suggest that gammaHV68 induces lymphomas via hit-and-run oncogenesis, paracrine effects, or stimulation of chronic inflammation.

MeSH Terms
Animals DNA, Viral/metabolism Gammaherpesvirinae/genetics,physiology Herpesviridae Infections/complications,pathology,virology Lymphoma/complications,genetics,pathology Lymphoproliferative Disorders/complications,genetics,pathology,virology Mice Mice, Inbred BALB C Mice, Knockout Spleen/cytology beta 2-Microglobulin/deficiency
Chemicals
DNA, Viral beta 2-Microglobulin
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Tarakanova Vera L
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Suarez Felipe
Tibbetts Scott A
Jacoby Meagan A
Weck Karen E
Hess Jay L
Speck Samuel H
Virgin Herbert W
References (71)
71 references, click to expand
  1. Immunological control of a murine gammaherpesvirus independent of CD8+ T cells.
    J Gen Virol. 1999 Feb;80 ( Pt 2):477-83 PMID: 10073710
  2. Macrophages are the major reservoir of latent murine gammaherpesvirus 68 in peritoneal cells.
    J Virol. 1999 Apr;73(4):3273-83 PMID: 10074181
  3. CD4(+) T cell-mediated control of a gamma-herpesvirus in B cell-deficient mice is mediated by IFN-gamma.
    Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):5135-40 PMID: 10220431
  4. B cells regulate murine gammaherpesvirus 68 latency.
    J Virol. 1999 Jun;73(6):4651-61 PMID: 10233924
  5. Herpesvirus saimiri as a model for gammaherpesvirus oncogenesis.
    Semin Cancer Biol. 1999 Jun;9(3):231-9 PMID: 10343074
  6. Apparent MHC-independent stimulation of CD8+ T cells in vivo during latent murine gammaherpesvirus infection.
    J Immunol. 1999 Aug 1;163(3):1481-9 PMID: 10415050
  7. Kinetic and phenotypic changes in murine lymphocytes infected with murine gammaherpesvirus-68 in vitro.
    J Gen Virol. 1999 Oct;80 ( Pt 10):2729-36 PMID: 10573167
  8. Gammaherpesviruses and "Hit-and-Run" oncogenesis.
    Am J Pathol. 2000 Jan;156(1):1-3 PMID: 10623645
  9. Transgenic expression of the chemokine receptor encoded by human herpesvirus 8 induces an angioproliferative disease resembling Kaposi's sarcoma.
    J Exp Med. 2000 Feb 7;191(3):445-54 PMID: 10662790
  10. NK cell recognition of non-classical HLA class I molecules.
    Semin Immunol. 2000 Apr;12(2):109-19 PMID: 10764619
  11. Latent murine gamma-herpesvirus infection is established in activated B cells, dendritic cells, and macrophages.
    J Immunol. 2000 Jul 15;165(2):1074-81 PMID: 10878386
  12. Control of gammaherpesvirus latency by latent antigen-specific CD8(+) T cells.
    J Exp Med. 2000 Oct 2;192(7):943-52 PMID: 11015436
  13. Development of spontaneous mammary tumors in BALB/c p53 heterozygous mice. A model for Li-Fraumeni syndrome.
    Am J Pathol. 2000 Dec;157(6):2151-9 PMID: 11106587
  14. Regression of a murine gammaherpesvirus 68-positive b-cell lymphoma mediated by CD4 T lymphocytes.
    J Virol. 2001 Apr;75(7):3480-2 PMID: 11238875
  15. A gene polymorphism associated with posttransplant lymphoproliferative disorder.
    Transplant Proc. 2001 Feb-Mar;33(1-2):1834 PMID: 11267533
  16. Elevated breast cancer risk in irradiated BALB/c mice associates with unique functional polymorphism of the Prkdc (DNA-dependent protein kinase catalytic subunit) gene.
    Cancer Res. 2001 Mar 1;61(5):1820-4 PMID: 11280730
  17. EBV-specific CD8+ T cell memory: relationships between epitope specificity, cell phenotype, and immediate effector function.
    J Immunol. 2001 Aug 15;167(4):2019-29 PMID: 11489984
  18. Antibody-mediated control of persistent gamma-herpesvirus infection.
    J Immunol. 2002 Apr 15;168(8):3958-64 PMID: 11937552
  19. Immune control of the number and reactivation phenotype of cells latently infected with a gammaherpesvirus.
    J Virol. 2002 Jul;76(14):7125-32 PMID: 12072512
  20. Antibody to a lytic cycle viral protein decreases gammaherpesvirus latency in B-cell-deficient mice.
    J Virol. 2002 Nov;76(22):11460-8 PMID: 12388707
  21. Effective vaccination against long-term gammaherpesvirus latency.
    J Virol. 2003 Feb;77(4):2522-9 PMID: 12551990
  22. Establishment and maintenance of gammaherpesvirus latency are independent of infective dose and route of infection.
    J Virol. 2003 Jul;77(13):7696-701 PMID: 12805472
  23. 10 years of mouse cancer modifier loci: human relevance.
    Cancer Res. 2003 Jun 15;63(12):3011-8 PMID: 12810618
  24. 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. 2003 Aug;77(15):8310-21 PMID: 12857900
  25. Virological and pathological features of mice infected with murine gamma-herpesvirus 68.
    J Gen Virol. 1992 Sep;73 ( Pt 9):2347-56 PMID: 1328491
  26. Murine gammaherpesvirus 68 establishes a latent infection in mouse B lymphocytes in vivo.
    J Gen Virol. 1992 Dec;73 ( Pt 12):3275-9 PMID: 1469366
  27. Kaposi's sarcoma-associated herpesvirus (KSHV)/human herpesvirus 8 (HHV-8) as a tumour virus.
    Herpes. 2003 Dec;10(3):72-7 PMID: 14759339
  28. Sustained CD8+ T-cell immune response to a novel immunodominant HLA-B*0702-associated epitope derived from an Epstein-Barr virus helicase-primase-associated protein.
    J Med Virol. 2004 Apr;72(4):635-45 PMID: 14981767
  29. Persistence of the Epstein-Barr virus and the origins of associated lymphomas.
    N Engl J Med. 2004 Mar 25;350(13):1328-37 PMID: 15044644
  30. Remarkably similar antigen receptors among a subset of patients with chronic lymphocytic leukemia.
    J Clin Invest. 2004 Apr;113(7):1008-16 PMID: 15057307
  31. Human neonatal Fc receptor mediates transport of IgG into luminal secretions for delivery of antigens to mucosal dendritic cells.
    Immunity. 2004 Jun;20(6):769-83 PMID: 15189741
  32. An optimized CD4 T-cell response can control productive and latent gammaherpesvirus infection.
    J Virol. 2004 Jul;78(13):6827-35 PMID: 15194758
  33. Oncogenic gamma-herpesviruses: comparison of viral proteins involved in tumorigenesis.
    Nat Rev Microbiol. 2004 Aug;2(8):656-68 PMID: 15263900
  34. A nonclassical MHC class I molecule restricts CTL-mediated rejection of a syngeneic melanoma tumor.
    J Immunol. 2004 Oct 1;173(7):4394-401 PMID: 15383569
  35. Pathogenetical characterization of isolate MHV-60 of mouse herpesvirus strain 68.
    Acta Virol. 2004;48(2):91-6 PMID: 15462284
  36. IFN-gamma gene polymorphisms associate with development of EBV+ lymphoproliferative disease in hu PBL-SCID mice.
    Blood. 2005 Feb 15;105(4):1558-65 PMID: 15498860
  37. Epstein-Barr virus: 40 years on.
    Nat Rev Cancer. 2004 Oct;4(10):757-68 PMID: 15510157
  38. Helicobacter infection, chronic inflammation, and the development of malignancy.
    Curr Opin Gastroenterol. 2005 Jan;21(1):32-8 PMID: 15687882
  39. A critical function for type I interferons in cancer immunoediting.
    Nat Immunol. 2005 Jul;6(7):722-9 PMID: 15951814
  40. Role of B-cell proliferation in the establishment of gammaherpesvirus latency.
    J Virol. 2005 Aug;79(15):9480-91 PMID: 16014911
  41. Virus-transformed pre-B cells show ordered activation but not inactivation of immunoglobulin gene rearrangement and transcription.
    J Exp Med. 1991 Mar 1;173(3):711-20 PMID: 1900081
  42. Beta 2-microglobulin deficient mice lack CD4-8+ cytolytic T cells.
    Nature. 1990 Apr 19;344(6268):742-6 PMID: 2139497
  43. 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
  44. An apparently new herpesvirus from primary kidney cultures of the squirrel monkey (Saimiri sciureus).
    Lab Anim Care. 1968 Jun;18(3):374-81 PMID: 4233372
  45. Herpesvirus saimiri. II. Experimentally induced malignant lymphoma in primates.
    Lab Anim Care. 1969 Jun;19(3):378-86 PMID: 4240129
  46. The susceptibility of various strains of neonatal mice to the carcinogenic effects of 9,10-dimethyl-1,2-benzanthracene.
    Eur J Cancer. 1968 Dec;4(6):579-85 PMID: 5717955
  47. Isolation of five strains of herpesviruses from two species of free living small rodents.
    Acta Virol. 1980 Dec;24(6):468 PMID: 6111210
  48. Lymphoproliferative disease in mice infected with murine gammaherpesvirus 68.
    Am J Pathol. 1994 Oct;145(4):818-26 PMID: 7943173
  49. Pathogenesis of murine gammaherpesvirus infection in mice deficient in CD4 and CD8 T cells.
    J Virol. 1993 Sep;67(9):5247-52 PMID: 8394447
  50. Interactions of murine gammaherpesvirus 68 with B and T cell lines.
    Virology. 1993 Apr;193(2):825-33 PMID: 8460488
  51. Abnormally short serum half-lives of IgG in beta 2-microglobulin-deficient mice.
    Eur J Immunol. 1996 Mar;26(3):690-6 PMID: 8605939
  52. Murine gammaherpesvirus-induced splenomegaly: a critical role for CD4 T cells.
    J Gen Virol. 1996 Apr;77 ( Pt 4):627-30 PMID: 8627250
  53. 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
  54. Absence of human herpesvirus 8 DNA sequences in neoplastic Kaposi's sarcoma cell lines.
    J Acquir Immune Defic Syndr Hum Retrovirol. 1996 Oct 1;13(2):194-7 PMID: 8862285
  55. Defective iron homeostasis in beta 2-microglobulin knockout mice recapitulates hereditary hemochromatosis in man.
    J Exp Med. 1996 Nov 1;184(5):1975-85 PMID: 8920884
  56. Progressive loss of CD8+ T cell-mediated control of a gamma-herpesvirus in the absence of CD4+ T cells.
    J Exp Med. 1996 Sep 1;184(3):863-71 PMID: 9064346
  57. Human cytomagalovirus IE1 and IE2 proteins are mutagenic and mediate "hit-and-run" oncogenic transformation in cooperation with the adenovirus E1A proteins.
    Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3341-5 PMID: 9096395
  58. Complete sequence and genomic analysis of murine gammaherpesvirus 68.
    J Virol. 1997 Aug;71(8):5894-904 PMID: 9223479
  59. Murine gammaherpesvirus 68 encodes tRNA-like sequences which are expressed during latency.
    J Gen Virol. 1997 Jul;78 ( Pt 7):1675-87 PMID: 9225045
  60. Disappearance of the Epstein-Barr virus in a relapse of Hodgkin's disease.
    J Pathol. 1997 Aug;182(4):475-9 PMID: 9306970
  61. Reduced incidence of Epstein-Barr virus-associated posttransplant lymphoproliferative disorder using preemptive antiviral therapy.
    Transplantation. 1997 Sep 27;64(6):848-52 PMID: 9326409
  62. Association of Kaposi's sarcoma-associated herpesvirus-positive primary effusion lymphoma with expression of the CD138/syndecan-1 antigen.
    Blood. 1997 Dec 15;90(12):4894-900 PMID: 9389706
  63. 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
  64. G-protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator.
    Nature. 1998 Jan 1;391(6662):86-9 PMID: 9422510
  65. The morphologic and molecular genetic categories of posttransplantation lymphoproliferative disorders are clinically relevant.
    Cancer. 1998 May 15;82(10):1978-87 PMID: 9587133
  66. Spontaneous loss of viral episomes accompanying Epstein-Barr virus reactivation in a Burkitt's lymphoma cell line.
    J Infect Dis. 1998 Jun;177(6):1705-9 PMID: 9607853
  67. Lung epithelial cells are a major site of murine gammaherpesvirus persistence.
    J Exp Med. 1998 Jun 15;187(12):1941-51 PMID: 9625754
  68. Malignant transformation of early lymphoid progenitors in mice expressing an activated Blk tyrosine kinase.
    Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7351-6 PMID: 9636152
  69. Beta 2-microglobulin knockout mice are highly susceptible to polyoma virus tumorigenesis.
    Virology. 1998 Dec 5;252(1):275-84 PMID: 9875336
  70. Non-antigen-specific B-cell activation following murine gammaherpesvirus infection is CD4 independent in vitro but CD4 dependent in vivo.
    J Virol. 1999 Feb;73(2):1075-9 PMID: 9882308
  71. Analysis of murine gammaherpesvirus-68 transcription during lytic and latent infection.
    J Gen Virol. 1999 Jan;80 ( Pt 1):75-82 PMID: 9934687
Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
0022-538X
DOI
10.1128/JVI.79.23.14668-14679.2005
Published
2005-12-00
Pages
14668-79
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC1287585
Subset
IM
Grants
NCI NIH HHS · T32 CA 09547 · United States
NCI NIH HHS · T32 CA009547 · United States
NCI NIH HHS · CA74730 · United States
NIAID NIH HHS · F32 AI065079-01 · United States
NCI NIH HHS · R01 CA074730 · United States
NIDDK NIH HHS · P30 DK52514 · United States
NIAID NIH HHS · F32 AI065079 · United States
External Links
PubMed source DOI: 10.1128/JVI.79.23.14668-14679.2005 PMC Full Text View journal details
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