1887

Abstract

Bovine leukemia virus (BLV) induces abnormal B-cell proliferation and B-cell lymphoma in cattle, where the BLV provirus is integrated into the host genome. BLV-infected B-cells rarely express viral proteins , but short-term cultivation augments BLV expression in some, but not all, BLV-infected B-cells. This observation suggests that two subsets, i.e. BLV-silencing cells and BLV-expressing cells, are present among BLV-infected B-cells, although the mechanisms of viral expression have not been determined. In this study, we examined B-cell markers and viral antigen expression in B-cells from BLV-infected cattle to identify markers that may discriminate BLV-expressing cells from BLV-silencing cells. The proportions of IgM B-cells were increased in blood lymphocytes from BLV-infected cattle. IgM B-cells mainly expressed BLV antigens, whereas IgM B-cells did not, although the provirus load was equivalent in both subsets. Several parameters were investigated in these two subsets to characterize their cellular behaviour. Real-time PCR and microarray analyses detected higher expression levels of some proto-oncogenes (e.g. , and ) in IgM B-cells than those in IgM B-cells. Moreover, lymphoma cells obtained from the lymph nodes of 14 BLV-infected cattle contained IgM or IgM B-cells but no IgM B-cells. To our knowledge, this is the first study to demonstrate that IgM B-cells mainly comprise BLV-expressing cells, whereas IgM B-cells comprise a high proportion of BLV-silencing B-cells in BLV-infected cattle.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.065011-0
2014-08-01
2020-10-28
Loading full text...

Full text loading...

/deliver/fulltext/jgv/95/8/1832.html?itemId=/content/journal/jgv/10.1099/vir.0.065011-0&mimeType=html&fmt=ahah

References

  1. Akl H., Badran B., Dobirta G., Manfouo-Foutsop G., Moschitta M., Merimi M., Burny A., Martiat P., Willard-Gallo K. E. 2007; Progressive loss of CD3 expression after HTLV-I infection results from chromatin remodeling affecting all the CD3 genes and persists despite early viral genes silencing. Virol J 4:85 [CrossRef][PubMed]
    [Google Scholar]
  2. Anastas J. N., Moon R. T. 2013; WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer 13:11–26 [CrossRef][PubMed]
    [Google Scholar]
  3. Arase H., Mocarski E. S., Campbell A. E., Hill A. B., Lanier L. L. 2002; Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science 296:1323–1326 [CrossRef][PubMed]
    [Google Scholar]
  4. Asquith B., Mosley A. J., Heaps A., Tanaka Y., Taylor G. P., McLean A. R., Bangham C. R. 2005; Quantification of the virus–host interaction in human T lymphotropic virus I infection. Retrovirology 2:75 [CrossRef][PubMed]
    [Google Scholar]
  5. Burger J. A. 2010; Chemokines and chemokine receptors in chronic lymphocytic leukemia (CLL): from understanding the basics towards therapeutic targeting. Semin Cancer Biol 20:424–430 [CrossRef][PubMed]
    [Google Scholar]
  6. Cambier J. C., Gauld S. B., Merrell K. T., Vilen B. J. 2007; B-cell anergy: from transgenic models to naturally occurring anergic B cells?. Nat Rev Immunol 7:633–643 [CrossRef][PubMed]
    [Google Scholar]
  7. Charles E. D., Brunetti C., Marukian S., Ritola K. D., Talal A. H., Marks K., Jacobson I. M., Rice C. M., Dustin L. B. 2011; Clonal B cells in patients with hepatitis C virus-associated mixed cryoglobulinemia contain an expanded anergic CD21low B-cell subset. Blood 117:5425–5437 [CrossRef][PubMed]
    [Google Scholar]
  8. Chung E. Y., Psathas J. N., Yu D., Li Y., Weiss M. J., Thomas-Tikhonenko A. 2012; CD19 is a major B cell receptor-independent activator of MYC-driven B-lymphomagenesis. J Clin Invest 122:2257–2266 [CrossRef][PubMed]
    [Google Scholar]
  9. Copeland K. F., Haaksma A. G., Goudsmit J., Heeney J. L. 1994; Calcium-mediated inhibition of phorbol ester and Tax trans-activation of the human T cell leukaemia virus type 1. J Gen Virol 75:1623–1631 [CrossRef][PubMed]
    [Google Scholar]
  10. Depoil D., Fleire S., Treanor B. L., Weber M., Harwood N. E., Marchbank K. L., Tybulewicz V. L., Batista F. D. 2008; CD19 is essential for B cell activation by promoting B cell receptor-antigen microcluster formation in response to membrane-bound ligand. Nat Immunol 9:63–72 [CrossRef][PubMed]
    [Google Scholar]
  11. Dequiedt F., Hanon E., Kerkhofs P., Pastoret P. P., Portetelle D., Burny A., Kettmann R., Willems L. 1997; Both wild-type and strongly attenuated bovine leukemia viruses protect peripheral blood mononuclear cells from apoptosis. J Virol 71:630–639[PubMed]
    [Google Scholar]
  12. Derse D., Hill S. A., Lloyd P. A., Chung H.-K., Morse B. A. 2001; Examining human T-lymphotropic virus type 1 infection and replication by cell-free infection with recombinant virus vectors. J Virol 75:8461–8468 [CrossRef][PubMed]
    [Google Scholar]
  13. Eychène A., Rocques N., Pouponnot C. 2008; A new MAFia in cancer. Nat Rev Cancer 8:683–693 [CrossRef][PubMed]
    [Google Scholar]
  14. Feuer G., Fraser J. K., Zack J. A., Lee F., Feuer R., Chen I. S. 1996; Human T-cell leukemia virus infection of human hematopoietic progenitor cells: maintenance of virus infection during differentiation in vitro and in vivo. J Virol 70:4038–4044[PubMed]
    [Google Scholar]
  15. Florins A., de Brogniez A., Elemans M., Bouzar A.-B., François C., Reichert M., Asquith B., Willems L. 2012; Viral expression directs the fate of B cells in bovine leukemia virus-infected sheep. J Virol 86:621–624 [CrossRef][PubMed]
    [Google Scholar]
  16. Fulton B. E. Jr, Portella M., Radke K. 2006; Dissemination of bovine leukemia virus-infected cells from a newly infected sheep lymph node. J Virol 80:7873–7884 [CrossRef][PubMed]
    [Google Scholar]
  17. Gatot J.-S., Callebaut I., Mornon J. P., Portetelle D., Burny A., Kerkhofs P., Kettmann R., Willems L. 1998; Conservative mutations in the immunosuppressive region of the bovine leukemia virus transmembrane protein affect fusion but not infectivity in vivo. J Biol Chem 273:12870–12880 [CrossRef][PubMed]
    [Google Scholar]
  18. Ghez D., Lepelletier Y., Lambert S., Fourneau J.-M., Blot V., Janvier S., Arnulf B., van Endert P. M., Heveker N.other authors 2006; Neuropilin-1 is involved in human T-cell lymphotropic virus type 1 entry. J Virol 80:6844–6854 [CrossRef][PubMed]
    [Google Scholar]
  19. Gillet N., Florins A., Boxus M., Burteau C., Nigro A., Vandermeers F., Balon H., Bouzar A. B., Defoiche J.other authors 2007; Mechanisms of leukemogenesis induced by bovine leukemia virus: prospects for novel anti-retroviral therapies in human. Retrovirology 4:18 [CrossRef][PubMed]
    [Google Scholar]
  20. Griebel P. J., Kennedy L., Graham T., Davis W. C., Reynolds J. D. 1992; Characterization of B-cell phenotypic changes during ileal and jejunal Peyer’s patch development in sheep. Immunology 77:564–570[PubMed]
    [Google Scholar]
  21. Hanon E., Asquith R. E., Taylor G. P., Tanaka Y., Weber J. N., Bangham C. R. 2000; High frequency of viral protein expression in human T cell lymphotropic virus type 1-infected peripheral blood mononuclear cells. AIDS Res Hum Retroviruses 16:1711–1715 [CrossRef][PubMed]
    [Google Scholar]
  22. Hasegawa H., Sawa H., Lewis M. J., Orba Y., Sheehy N., Yamamoto Y., Ichinohe T., Tsunetsugu-Yokota Y., Katano H.other authors 2006; Thymus-derived leukemia-lymphoma in mice transgenic for the Tax gene of human T-lymphotropic virus type I. Nat Med 12:466–472 [CrossRef][PubMed]
    [Google Scholar]
  23. Igakura T., Stinchcombe J. C., Goon P. K. C., Taylor G. P., Weber J. N., Griffiths G. M., Tanaka Y., Osame M., Bangham C. R. M. 2003; Spread of HTLV-I between lymphocytes by virus-induced polarization of the cytoskeleton. Science 299:1713–1716 [CrossRef][PubMed]
    [Google Scholar]
  24. Ikebuchi R., Konnai S., Shirai T., Sunden Y., Murata S., Onuma M., Ohashi K. 2011; Increase of cells expressing PD-L1 in bovine leukemia virus infection and enhancement of anti-viral immune responses in vitro via PD-L1 blockade. Vet Res 42:103 [CrossRef][PubMed]
    [Google Scholar]
  25. Ikebuchi R., Konnai S., Okagawa T., Yokoyama K., Nakajima C., Suzuki Y., Murata S., Ohashi K. 2013; Blockade of bovine PD-1 increases T cell function and inhibits bovine leukemia virus expression in B cells in vitro. Vet Res 44:59 [CrossRef][PubMed]
    [Google Scholar]
  26. Ikebuchi R., Konnai S., Okagawa T., Yokoyama K., Nakajima C., Suzuki Y., Murata S., Ohashi K. 2014; Influence of PD-L1 cross-linking on cell death in PD-L1-expressing cell lines and bovine lymphocytes. Immunology [Epub ahead of print] [CrossRef][PubMed]
    [Google Scholar]
  27. Isnardi I., Ng Y.-S., Menard L., Meyers G., Saadoun D., Srdanovic I., Samuels J., Berman J., Buckner J. H.other authors 2010; Complement receptor 2/CD21- human naive B cells contain mostly autoreactive unresponsive clones. Blood 115:5026–5036 [CrossRef][PubMed]
    [Google Scholar]
  28. Jochum W., Passegué E., Wagner E. F. 2001; AP-1 in mouse development and tumorigenesis. Oncogene 20:2401–2412 [CrossRef][PubMed]
    [Google Scholar]
  29. Johnston E. R., Powers M. A., Kidd L. C., Radke K. 1996; Peripheral blood mononuclear cells from sheep infected with a variant of bovine leukemia virus synthesize envelope glycoproteins but fail to induce syncytia in culture. J Virol 70:6296–6303[PubMed]
    [Google Scholar]
  30. Jonkers J., Korswagen H. C., Acton D., Breuer M., Berns A. 1997; Activation of a novel proto-oncogene, Frat1, contributes to progression of mouse T-cell lymphomas. EMBO J 16:441–450 [CrossRef][PubMed]
    [Google Scholar]
  31. Kerkhofs P., Adam E., Droogmans L., Portetelle D., Mammerickx M., Burny A., Kettmann R., Willems L. 1996; Cellular pathways involved in the ex vivo expression of bovine leukemia virus. J Virol 70:2170–2177[PubMed]
    [Google Scholar]
  32. Kidd L. C., Radke K. 1996; Lymphocyte activators elicit bovine leukemia virus expression differently as asymptomatic infection progresses. Virology 217:167–177 [CrossRef][PubMed]
    [Google Scholar]
  33. Kobayashi S., Tian Y., Ohno N., Yuji K., Ishigaki T., Isobe M., Tsuda M., Oyaizu N., Watanabe E.other authors 2013; The CD3 versus CD7 plot in multicolor flow cytometry reflects progression of disease stage in patients infected with HTLV-I. PLoS ONE 8:e53728 [CrossRef][PubMed]
    [Google Scholar]
  34. Küppers R. 2003; B cells under influence: transformation of B cells by Epstein–Barr virus. Nat Rev Immunol 3:801–812 [CrossRef][PubMed]
    [Google Scholar]
  35. Lagarias D. M., Radke K. 1989; Transcriptional activation of bovine leukemia virus in blood cells from experimentally infected, asymptomatic sheep with latent infections. J Virol 63:2099–2107[PubMed]
    [Google Scholar]
  36. Lavanya M., Kinet S., Montel-Hagen A., Mongellaz C., Battini J. L., Sitbon M., Taylor N. 2008; Cell surface expression of the bovine leukemia virus-binding receptor on B and T lymphocytes is induced by receptor engagement. J Immunol 181:891–898 [CrossRef][PubMed]
    [Google Scholar]
  37. Manel N., Kim F. J., Kinet S., Taylor N., Sitbon M., Battini J. L. 2003; The ubiquitous glucose transporter GLUT-1 is a receptor for HTLV. Cell 115:449–459 [CrossRef][PubMed]
    [Google Scholar]
  38. Meirom R., Moss S., Brenner J. 1997; Bovine leukemia virus-gp51 antigen expression is associated with CD5 and IgM markers on infected lymphocytes. Vet Immunol Immunopathol 59:113–119 [CrossRef][PubMed]
    [Google Scholar]
  39. Merimi M., Klener P., Szynal M., Cleuter Y., Bagnis C., Kerkhofs P., Burny A., Martiat P., Van den Broeke A. 2007a; Complete suppression of viral gene expression is associated with the onset and progression of lymphoid malignancy: observations in bovine leukemia virus-infected sheep. Retrovirology 4:51 [CrossRef][PubMed]
    [Google Scholar]
  40. Merimi M., Klener P., Szynal M., Cleuter Y., Kerkhofs P., Burny A., Martiat P., Van den Broeke A. 2007b; Suppression of viral gene expression in bovine leukemia virus-associated B-cell malignancy: interplay of epigenetic modifications leading to chromatin with a repressive histone code. J Virol 81:5929–5939 [CrossRef][PubMed]
    [Google Scholar]
  41. Milde-Langosch K. 2005; The Fos family of transcription factors and their role in tumourigenesis. Eur J Cancer 41:2449–2461 [CrossRef][PubMed]
    [Google Scholar]
  42. Mirsky M. L., Olmstead C. A., Da Y., Lewin H. A. 1996; The prevalence of proviral bovine leukemia virus in peripheral blood mononuclear cells at two subclinical stages of infection. J Virol 70:2178–2183[PubMed]
    [Google Scholar]
  43. Mukwedeya D. T., Takamatsu H., Parkhouse R. M. E. 1993; Identification of bovine B cell reactive and B cell specific monoclonal antibodies. Vet Immunol Immunopathol 39:177–186 [CrossRef][PubMed]
    [Google Scholar]
  44. Naessens J., Howard C. J., Hopkins J. 1997; Nomenclature and characterization of leukocyte differentiation antigens in ruminants. Immunol Today 18:365–368 [CrossRef][PubMed]
    [Google Scholar]
  45. Niwa H., Yamamura K., Miyazaki J. 1991; Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene 108:193–199 [CrossRef][PubMed]
    [Google Scholar]
  46. Powers M. A., Radke K. 1992; Activation of bovine leukemia virus transcription in lymphocytes from infected sheep: rapid transition through early to late gene expression. J Virol 66:4769–4777[PubMed]
    [Google Scholar]
  47. Quách T. D., Manjarrez-Orduño N., Adlowitz D. G., Silver L., Yang H., Wei C., Milner E. C., Sanz I. 2011; Anergic responses characterize a large fraction of human autoreactive naive B cells expressing low levels of surface IgM. J Immunol 186:4640–4648 [CrossRef][PubMed]
    [Google Scholar]
  48. Sagata N., Yasunaga T., Tsuzuku-Kawamura J., Ohishi K., Ogawa Y., Ikawa Y. 1985; Complete nucleotide sequence of the genome of bovine leukemia virus: its evolutionary relationship to other retroviruses. Proc Natl Acad Sci U S A 82:677–681 [CrossRef][PubMed]
    [Google Scholar]
  49. Saito Y. D., Jensen A. R., Salgia R., Posadas E. M. 2010; Fyn: a novel molecular target in cancer. Cancer 116:1629–1637 [CrossRef][PubMed]
    [Google Scholar]
  50. Schwartz I., Bensaid A., Polack B., Perrin B., Berthelemy M., Levy D. 1994; In vivo leukocyte tropism of bovine leukemia virus in sheep and cattle. J Virol 68:4589–4596[PubMed]
    [Google Scholar]
  51. So L., Fruman D. A. 2012; PI3K signalling in B- and T-lymphocytes: new developments and therapeutic advances. Biochem J 442:465–481 [CrossRef][PubMed]
    [Google Scholar]
  52. Teague B. N., Pan Y., Mudd P. A., Nakken B., Zhang Q., Szodoray P., Kim-Howard X., Wilson P. C., Farris A. D. 2007; Cutting edge: transitional T3 B cells do not give rise to mature B cells, have undergone selection, and are reduced in murine lupus. J Immunol 178:7511–7515 [CrossRef][PubMed]
    [Google Scholar]
  53. Trentin L., Cabrelle A., Facco M., Carollo D., Miorin M., Tosoni A., Pizzo P., Binotto G., Nicolardi L.other authors 2004; Homeostatic chemokines drive migration of malignant B cells in patients with non-Hodgkin lymphomas. Blood 104:502–508 [CrossRef][PubMed]
    [Google Scholar]
  54. Van den Broeke A., Cleuter Y., Chen G., Portetelle D., Mammerickx M., Zagury D., Fouchard M., Coulombel L., Kettmann R., Burny A. 1988; Even transcriptionally competent proviruses are silent in bovine leukemia virus-induced sheep tumor cells. Proc Natl Acad Sci U S A 85:9263–9267 [CrossRef][PubMed]
    [Google Scholar]
  55. Willard-Gallo K. E., Furtado M., Burny A., Wolinsky S. M. 2001; Down-modulation of TCR/CD3 surface complexes after HIV-1 infection is associated with differential expression of the viral regulatory genes. Eur J Immunol 31:969–979 [CrossRef][PubMed]
    [Google Scholar]
  56. Yasuda M., Jenne C. N., Kennedy L. J., Reynolds J. D. 2006; The sheep and cattle Peyer’s patch as a site of B-cell development. Vet Res 37:401–415 [CrossRef][PubMed]
    [Google Scholar]
  57. Zikherman J., Parameswaran R., Weiss A. 2012; Endogenous antigen tunes the responsiveness of naive B cells but not T cells. Nature 489:160–164 [CrossRef][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.065011-0
Loading
/content/journal/jgv/10.1099/vir.0.065011-0
Loading

Data & Media loading...

Most cited this month Most Cited RSS feed

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