Murine Gamma-herpesvirus Immortalization of Fetal Liver-Derived B Cells Requires both the Viral Cyclin D Homolog and Latency-Associated Nuclear Antigen

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Human gammaherpesviruses are associated with the development of lymphoproliferative diseases and B cell lymphomas, particularly in immunosuppressed hosts. Understanding the molecular mechanisms by which human gammaherpesviruses cause disease is hampered by the lack of convenient small animal models to study them. However, infection of laboratory strains of mice with the rodent virus murine gammaherpesvirus 68 (MHV68) has been useful in gaining insights into how gammaherpesviruses contribute to the genesis and progression of lymphoproliferative lesions. In this report we make the novel observation that MHV68 infection of murine day 15 fetal liver cells results in their immortalization and differentiation into B plasmablasts that can be propagated indefinitely in vitro, and can establish metastasizing lymphomas in mice lacking normal immune competence. The phenotype of the MHV68 immortalized B cell lines is similar to that observed in lymphomas caused by KSHV and resembles the favored phenotype observed during MHV68 infection in vivo. All established cell lines maintained the MHV68 genome, with limited viral gene expression and little or no detectable virus production -⁠ although virus reactivation could be induced upon crosslinking surface Ig. Notably, transcription of the genes encoding the MHV68 viral cyclin D homolog (v-cyclin) and the homolog of the KSHV latency-associated nuclear antigen (LANA), both of which are conserved among characterized γ2-herpesviruses, could consistently be detected in the established B cell lines. Furthermore, we show that the v-cyclin and LANA homologs are required for MHV68 immortalization of murine B cells. In contrast the M2 gene, which is unique to MHV68 and plays a role in latency and virus reactivation in vivo, was dispensable for B cell immortalization. This new model of gammaherpesvirus-driven B cell immortalization and differentiation in a small animal model establishes an experimental system for detailed investigation of the role of gammaherpesvirus gene products and host responses in the genesis and progression of gammaherpesvirus-associated lymphomas, and presents a convenient system to evaluate therapeutic modalities.

Vyšlo v časopise: Murine Gamma-herpesvirus Immortalization of Fetal Liver-Derived B Cells Requires both the Viral Cyclin D Homolog and Latency-Associated Nuclear Antigen. PLoS Pathog 7(9): e32767. doi:10.1371/journal.ppat.1002220
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002220

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1. SpeckSHGanemD 2010 Viral latency and its regulation: lessons from the gamma-herpesviruses. Cell Host Microbe 8 100 115

2. YoungLSRickinsonAB 2004 Epstein-Barr virus: 40 years on. Nat Rev Cancer 4 757 768

3. Thorley-LawsonDAAlldayMJ 2008 The curious case of the tumour virus: 50 years of Burkitt's lymphoma. Nat Rev Microbiol 6 913 924

4. ChangYCesarmanEPessinMSLeeFCulpepperJ 1994 Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 266 1865 1869

5. CesarmanEChangYMoorePSSaidJWKnowlesDM 1995 Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med 332 1186 1191

6. CarboneACesarmanESpinaMGloghiniASchulzTF 2009 HIV-associated lymphomas and gamma-herpesviruses. Blood 113 1213 1224

7. JohnsonDRJondalM 1981 Herpesvirus-transformed cytotoxic T-cell lines. Nature 291 81 83

8. BiesingerBMuller-FleckensteinISimmerBLangGWittmannS 1992 Stable growth transformation of human T lymphocytes by herpesvirus saimiri. Proc Natl Acad Sci U S A 89 3116 3119

9. JarousseNChandranBCoscoyL 2008 Lack of heparan sulfate expression in B-cell lines: implications for Kaposi's sarcoma-associated herpesvirus and murine gammaherpesvirus 68 infections. J Virol 82 12591 12597

10. RaffMCMegsonMOwenJJCooperMD 1976 Early production of intracellular IgM by B-lymphocyte precursors in mouse. Nature 259 224 226

11. DenisKADorshkindKWitteON 1987 Regulated progression of B lymphocyte differentiation from cultured fetal liver. J Exp Med 166 391 403

12. GunjiYSudoTSudaJYamaguchiYNakauchiH 1991 Support of early B-cell differentiation in mouse fetal liver by stromal cells and interleukin-7. Blood 77 2612 2617

13. GodinIEGarcia-PorreroJACoutinhoADieterlen-LievreFMarcosMA 1993 Para-aortic splanchnopleura from early mouse embryos contains B1a cell progenitors. Nature 364 67 70

14. MartinezMJMinguetSGonzaloPSoroPGde AndresB 2001 Long-lived polyclonal B-cell lines derived from midgestation mouse embryo lymphohematopoietic progenitors reconstitute adult immunodeficient mice. Blood 98 1862 1871

15. LinQTaniuchiIKitamuraDWangJKearneyJF 1998 T and B cell development in BP-1/6C3/aminopeptidase A-deficient mice. J Immunol 160 4681 4687

16. RoweDT 1999 Epstein-Barr virus immortalization and latency. Front Biosci 4 D346 371

17. LiSCRothmanPBZhangJChanCHirshD 1994 Expression of I mu-C gamma hybrid germline transcripts subsequent to immunoglobulin heavy chain class switching. Int Immunol 6 491 497

18. MuramatsuMKinoshitaKFagarasanSYamadaSShinkaiY 2000 Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102 553 563

19. WhitlockCAZieglerSFTreimanLJStaffordJIWitteON 1983 Differentiation of cloned populations of immature B cells after transformation with Abelson murine leukemia virus. Cell 32 903 911

20. ForrestJCSpeckSH 2008 Establishment of B-cell lines latently infected with reactivation-competent murine gammaherpesvirus 68 provides evidence for viral alteration of a DNA damage-signaling cascade. J Virol 82 7688 7699

21. MillerG 1990 The switch between latency and replication of Epstein-Barr virus. J Infect Dis 161 833 844

22. KingWVan SantenVKieffE 1981 Epstein-Barr virus RNA. VI. Viral RNA in restringently and abortively infected Raji cells. J Virol 38 649 660

23. van DykLFHessJLKatzJDJacobyMSpeckSH 1999 The murine gammaherpesvirus 68 v-cyclin gene is an oncogene that promotes cell cycle progression in primary lymphocytes. J Virol 73 5110 5122

24. SiegelAMHerskowitzJHSpeckSH 2008 The MHV68 M2 protein drives IL-10 dependent B cell proliferation and differentiation. PLoS Pathog 4 e1000039

25. HardyRRHayakawaK 1991 A developmental switch in B lymphopoiesis. Proc Natl Acad Sci U S A 88 11550 11554

26. HayakawaKHardyRRHerzenbergLAHerzenbergLA 1985 Progenitors for Ly-1 B cells are distinct from progenitors for other B cells. J Exp Med 161 1554 1568

27. MelkusMWEstesJDPadgett-ThomasAGatlinJDentonPW 2006 Humanized mice mount specific adaptive and innate immune responses to EBV and TSST-1. Nat Med 12 1316 1322

28. ShultzLDIshikawaFGreinerDL 2007 Humanized mice in translational biomedical research. Nat Rev Immunol 7 118 130

29. YajimaMImadomeKNakagawaAWatanabeSTerashimaK 2008 A new humanized mouse model of Epstein-Barr virus infection that reproduces persistent infection, lymphoproliferative disorder, and cell-mediated and humoral immune responses. J Infect Dis 198 673 682

30. GuoHGSadowskaMReidWTschachlerEHaywardG 2003 Kaposi's sarcoma-like tumors in a human herpesvirus 8 ORF74 transgenic mouse. J Virol 77 2631 2639

31. FakhariFDJeongJHKananYDittmerDP 2006 The latency-associated nuclear antigen of Kaposi sarcoma-associated herpesvirus induces B cell hyperplasia and lymphoma. J Clin Invest 116 735 742

32. PrakashOTangZYPengXColemanRGillJ 2002 Tumorigenesis and aberrant signaling in transgenic mice expressing the human herpesvirus-8 K1 gene. J Natl Cancer Inst 94 926 935

33. CaldwellRGWilsonJBAndersonSJLongneckerR 1998 Epstein-Barr virus LMP2A drives B cell development and survival in the absence of normal B cell receptor signals. Immunity 9 405 411

34. StunzLLBuschLKMunroeMESigmundCDTygrettLT 2004 Expression of the cytoplasmic tail of LMP1 in mice induces hyperactivation of B lymphocytes and disordered lymphoid architecture. Immunity 21 255 266

35. FakhariFDDittmerDP 2002 Charting latency transcripts in Kaposi's sarcoma-associated herpesvirus by whole-genome real-time quantitative PCR. J Virol 76 6213 6223

36. JennerRGAlbaMMBoshoffCKellamP 2001 Kaposi's sarcoma-associated herpesvirus latent and lytic gene expression as revealed by DNA arrays. J Virol 75 891 902

37. DittmerDP 2003 Transcription profile of Kaposi's sarcoma-associated herpesvirus in primary Kaposi's sarcoma lesions as determined by real-time PCR arrays. Cancer Res 63 2010 2015

38. Paulose-MurphyMHaNKXiangCChenYGillimL 2001 Transcription program of human herpesvirus 8 (kaposi's sarcoma-associated herpesvirus). J Virol 75 4843 4853

39. SugayaMWatanabeTYangAStarostMFKobayashiH 2005 Lymphatic dysfunction in transgenic mice expressing KSHV k-cyclin under the control of the VEGFR-3 promoter. Blood 105 2356 2363

40. VerschurenEWKlefstromJEvanGIJonesN 2002 The oncogenic potential of Kaposi's sarcoma-associated herpesvirus cyclin is exposed by p53 loss in vitro and in vivo. Cancer Cell 2 229 241

41. SarekGJarviluomaAOjalaPM 2006 KSHV viral cyclin inactivates p27KIP1 through Ser10 and Thr187 phosphorylation in proliferating primary effusion lymphomas. Blood 107 725 732

42. SuarezALvan DykLF 2008 Endothelial cells support persistent gammaherpesvirus 68 infection. PLoS Pathog 4 e1000152

43. RadkovSAKellamPBoshoffC 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

44. SinSHFakhariFDDittmerDP 2010 The viral latency-associated nuclear antigen augments the B-cell response to antigen in vivo. J Virol 84 10653 10660

45. FriborgJJrKongWHottigerMONabelGJ 1999 p53 inhibition by the LANA protein of KSHV protects against cell death. Nature 402 889 894

46. FujimuroMWuFYApRhysCKajumbulaHYoungDB 2003 A novel viral mechanism for dysregulation of beta-catenin in Kaposi's sarcoma-associated herpesvirus latency. Nat Med 9 300 306

47. AnFQCompitelloNHorwitzESramkoskiMKnudsenES 2005 The latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus modulates cellular gene expression and protects lymphoid cells from p16 INK4A-induced cell cycle arrest. J Biol Chem 280 3862 3874

48. ForrestJCPadenCRAllenRD3rdCollinsJSpeckSH 2007 ORF73-null murine gammaherpesvirus 68 reveals roles for mLANA and p53 in virus replication. J Virol 81 11957 11971

49. LuFDayLGaoSJLiebermanPM 2006 Acetylation of the latency-associated nuclear antigen regulates repression of Kaposi's sarcoma-associated herpesvirus lytic transcription. J Virol 80 5273 5282

50. PadenCRForrestJCMoormanNJSpeckSH 2010 Murine gammaherpesvirus 68 LANA is essential for virus reactivation from splenocytes but not long-term carriage of viral genome. J Virol 84 7214 7224

51. HummeSReisbachGFeederleRDelecluseHJBoussetK 2003 The EBV nuclear antigen 1 (EBNA1) enhances B cell immortalization several thousandfold. Proc Natl Acad Sci U S A 100 10989 10994

52. CuconatiAWhiteE 2002 Viral homologs of BCL-2: role of apoptosis in the regulation of virus infection. Genes Dev 16 2465 2478

53. GangappaSvan DykLFJewettTJSpeckSHVirginHWt 2002 Identification of the in vivo role of a viral bcl-2. J Exp Med 195 931 940

54. EXHwangSOhSLeeJSJeongJH 2009 Viral Bcl-2-mediated evasion of autophagy aids chronic infection of gammaherpesvirus 68. PLoS Pathog 5 e1000609

55. LiangXCollinsCMMendelJBIwakoshiNNSpeckSH 2009 Gammaherpesvirus-driven plasma cell differentiation regulates virus reactivation from latently infected B lymphocytes. PLoS Pathog 5 e1000677

56. WeckKEDal CantoAJGouldJDO′GuinAKRothKA 1997 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 3 1346 1353

57. CollinsCMBossJMSpeckSH 2009 Identification of infected B-cell populations by using a recombinant murine gammaherpesvirus 68 expressing a fluorescent protein. J Virol 83 6484 6493

58. WeckKEKimSSVirginHISpeckSH 1999 B cells regulate murine gammaherpesvirus 68 latency. J Virol 73 4651 4661