1887

Abstract

Epstein–Barr virus (EBV) is a ubiquitous human herpesvirus that is involved in the pathogenesis of a wide spectrum of malignant and non-malignant diseases. Strong evidence implicates T lymphocytes in the control of EBV replication and tumorigenesis, but cellular components of the innate immune system are poorly characterized in terms of their function in the development of EBV-specific immunity or interaction with the virus. This study demonstrates that EBV virions produced in epithelial cells surpass their B cell-derived counterparts in the capacity to enter monocytes and inhibit their development into dendritic cells (DCs). Different ratios of the gp42 and gH glycoproteins in the envelope of virions that were derived from major histocompatibility complex class II-positive or -negative cells accounted primarily for the differences in EBV tropism. EBV is shown to enter both monocytes and DCs, although the cells are susceptible to virus-induced apoptosis only if infected at early stages of DC differentiation. The purified gH/gL heterodimer binds efficiently to monocytes and DCs, but not to B cells, suggesting that high expression levels of a putative binding partner for gH contribute to virus entry. This entry takes place despite very low or undetectable expression of CD21, the canonical EBV receptor. These results indicate that the site of virus replication, either in B cells or epithelial cells, alters EBV tropism for monocytes and DCs. This results in a change in the virus's immunomodulating capacity and may have important implications for the regulation of virus–host interactions during primary and chronic EBV infection.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.80140-0
2004-10-01
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/jgv/85/10/vir852767.html?itemId=/content/journal/jgv/10.1099/vir.0.80140-0&mimeType=html&fmt=ahah

References

  1. Ascherio A., Munger K. L., Lennette E. T., Spiegelman D., Hernan M. A., Olek M. J., Hankinson S. E., Hunter D. J. 2001; Epstein-Barr virus antibodies and risk of multiple sclerosis: a prospective study. JAMA 286:3083–3088 [CrossRef]
    [Google Scholar]
  2. Becker Y. 2003; Immunological and regulatory functions of uninfected and virus infected immature and mature subtypes of dendritic cells – a review. Virus Genes 26:119–130 [CrossRef]
    [Google Scholar]
  3. Bickham K., Goodman K., Paludan C., Nikiforow S., Tsang M. L., Steinman R. M., Münz C. 2003; Dendritic cells initiate immune control of Epstein-Barr virus transformation of B lymphocytes in vitro. J Exp Med 198:1653–1663 [CrossRef]
    [Google Scholar]
  4. Borza C. M., Hutt-Fletcher L. M. 2002; Alternate replication in B cells and epithelial cells switches tropism of Epstein–Barr virus. Nat Med 8:594–599 [CrossRef]
    [Google Scholar]
  5. Conant M. A. 1987; Hairy leukoplakia. A new disease of the oral mucosa. Arch Dermatol 123:585–587 [CrossRef]
    [Google Scholar]
  6. D'Addario M., Ahmad A., Xu J. W., Menezes J. 1999; Epstein-Barr virus envelope glycoprotein gp350 induces NF- κ B activation and IL-1 β synthesis in human monocytes-macrophages involving PKC and PI3-K. FASEB J 13:2203–2213
    [Google Scholar]
  7. Daniels T. E., Greenspan D., Greenspan J. S., Lennette E., Schiodt M., Petersen V., de Souza Y. 1987; Absence of Langerhans cells in oral hairy leukoplakia, an AIDS-associated lesion. J Invest Dermatol 89:178–182 [CrossRef]
    [Google Scholar]
  8. Gosselin J., Menezes J., D'Addario M., Hiscott J., Flamand L., Lamoreux G., Oth D. 1991; Inhibition of tumor necrosis factor-alpha transcription by Epstein-Barr virus. Eur J Immunol 21:203–208 [CrossRef]
    [Google Scholar]
  9. Gosselin J., Flamand L., D'Addario M., Hiscott J., Stefanescu I., Ablashi D. V., Gallo R. C., Menezes J. 1992; Modulatory effects of Epstein-Barr, herpes simplex, and human herpes-6 viral infections and coinfections on cytokine synthesis. A comparative study. J Immunol 149:181–187
    [Google Scholar]
  10. Greenspan J. S., Greenspan D., Lennette E. T., Abrams D. I., Conant M. A., Petersen V., Freese U. K. 1985; Replication of Epstein-Barr virus within the epithelial cells of oral “hairy” leukoplakia, an AIDS-associated lesion. N Engl J Med 313:1564–1571 [CrossRef]
    [Google Scholar]
  11. Gustafsson Å., Levitsky V., Zou J.-Z. 7 other authors 2000; Epstein-Barr virus (EBV) load in bone marrow transplant recipients at risk to develop posttransplant lymphoproliferative disease: prophylactic infusion of EBV-specific cytotoxic T cells. Blood 95:807–814
    [Google Scholar]
  12. Haan K. M., Kwok W. W., Longnecker R., Speck P. 2000; Epstein-Barr virus entry utilizing HLA-DP or HLA-DQ as a coreceptor. J Virol 74:2451–2454 [CrossRef]
    [Google Scholar]
  13. Heid C. A., Stevens J., Livak K. J., Williams P. M. 1996; Real time quantitative PCR. Genome Res 6:986–994 [CrossRef]
    [Google Scholar]
  14. Herrmann K., Frangou P., Middeldorp J., Niedobitek G. 2002; Epstein–Barr virus replication in tongue epithelial cells. J Gen Virol 83:2995–2998
    [Google Scholar]
  15. Heslop H. E., Rooney C. M. 1997; Adoptive cellular immunotherapy for EBV lymphoproliferative diseases. Immunol Rev 157:217–222 [CrossRef]
    [Google Scholar]
  16. Heslop H. E., Ng C. Y. C., Li C., Smith C. A., Loftin S. K., Krance R. A., Brenner M. K., Rooney C. M. 1996; Long-term restoration of immunity against Epstein-Barr virus infection by adoptive transfer of gene-modified virus-specific T lymphocytes. Nat Med 2:551–555 [CrossRef]
    [Google Scholar]
  17. Hoffman G. J., Lazarowitz S. G., Hayward S. D. 1980; Monoclonal antibody against a 250,000-dalton glycoprotein of Epstein–Barr virus identifies a membrane antigen and a neutralizing antigen. Proc Natl Acad Sci U S A 77:2979–2983 [CrossRef]
    [Google Scholar]
  18. Klein G., Dombos L., Gothoskar B. 1972; Sensitivity of Epstein-Barr virus (EBV) producer and non-producer human lymphoblastoid cell lines to superinfection with EB-virus. Int J Cancer 10:44–57 [CrossRef]
    [Google Scholar]
  19. Kleinschmidt-DeMasters B. K., Gilden D. H. 2001; The expanding spectrum of herpesvirus infections of the nervous system. Brain Pathol 11:440–451 [CrossRef]
    [Google Scholar]
  20. Kobelt D., Lechmann M., Steinkasserer A. 2003; The interaction between dendritic cells and herpes simplex virus-1. Curr Top Microbiol Immunol 276:145–161
    [Google Scholar]
  21. Kouwenhoven M., Özenci V., Gomes A., Yarilin D., Giedraitis V., Press R., Link H. 2001; Multiple sclerosis: elevated expression of matrix metalloproteinases in blood monocytes. J Autoimmun 16:463–470 [CrossRef]
    [Google Scholar]
  22. Li Q., Turk S. M., Hutt-Fletcher L. M. 1995; The Epstein-Barr virus (EBV) BZLF2 gene product associates with the gH and gL homologs of EBV and carries an epitope critical to infection of B cells but not of epithelial cells. J Virol 69:3987–3994
    [Google Scholar]
  23. Li Q., Spriggs M. K., Kovats S., Turk S. M., Comeau M. R., Nepom B., Hutt-Fletcher L. M. 1997; Epstein-Barr virus uses HLA class II as a cofactor for infection of B lymphocytes. J Virol 71:4657–4662
    [Google Scholar]
  24. Li L., Masucci M. G., Levitsky V. 2000; Effect of interleukin-7 on the in vitro development and maturation of monocyte derived human dendritic cells. Scand J Immunol 51:361–371 [CrossRef]
    [Google Scholar]
  25. Li L., Liu D., Hutt-Fletcher L., Morgan A., Masucci M. G., Levitsky V. 2002; Epstein-Barr virus inhibits the development of dendritic cells by promoting apoptosis of their monocyte precursors in the presence of granulocyte macrophage-colony-stimulating factor and interleukin-4. Blood 99:3725–3734 [CrossRef]
    [Google Scholar]
  26. Mackett M., Conway M. J., Arrand J. R., Haddad R. S., Hutt-Fletcher L. M. 1990; Characterization and expression of a glycoprotein encoded by the Epstein-Barr virus Bam HI I fragment. J Virol 64:2545–2552
    [Google Scholar]
  27. Masy E., Adriaenssens E., Montpellier C. 9 other authors 2002; Human monocytic cell lines transformed in vitro by Epstein-Barr virus display a type II latency and LMP-1-dependent proliferation. J Virol 76:6460–6472 [CrossRef]
    [Google Scholar]
  28. Molesworth S. J., Lake C. M., Borza C. M., Turk S. M., Hutt-Fletcher L. M. 2000; Epstein-Barr virus gH is essential for penetration of B cells but also plays a role in attachment of virus to epithelial cells. J Virol 74:6324–6332 [CrossRef]
    [Google Scholar]
  29. Neuhierl B., Feederle R., Hammerschmidt W., Delecluse H. J. 2002; Glycoprotein gp110 of Epstein–Barr virus determines viral tropism and efficiency of infection. Proc Natl Acad Sci U S A 99:15036–15041 [CrossRef]
    [Google Scholar]
  30. Niedobitek G., Agathanggelou A., Herbst H., Whitehead L., Wright D. H., Young L. S. 1997; Epstein-Barr virus (EBV) infection in infectious mononucleosis: virus latency, replication and phenotype of EBV-infected cells. J Pathol 182:151–159 [CrossRef]
    [Google Scholar]
  31. Niedobitek G., Agathanggelou A., Steven N., Young L. S. 2000; Epstein-Barr virus (EBV) in infectious mononucleosis: detection of the virus in tonsillar B lymphocytes but not in desquamated oropharyngeal epithelial cells. Mol Pathol 53:37–42 [CrossRef]
    [Google Scholar]
  32. Oba D. E., Hutt-Fletcher L. M. 1988; Induction of antibodies to the Epstein-Barr virus glycoprotein gp85 with a synthetic peptide corresponding to a sequence in the BXLF2 open reading frame. J Virol 62:1108–1114
    [Google Scholar]
  33. Oda T., Imai S., Chiba S., Takada K. 2000; Epstein-Barr virus lacking glycoprotein gp85 cannot infect B cells and epithelial cells. Virology 276:52–58 [CrossRef]
    [Google Scholar]
  34. Peter J., Ray C. G. 1998; Infectious mononucleosis. Pediatr Rev 19:276–279 [CrossRef]
    [Google Scholar]
  35. Pulford D. J., Lowrey P., Morgan A. J. 1995; Co-expression of the Epstein–Barr virus BXLF2 and BKRF2 genes with a recombinant baculovirus produces gp85 on the cell surface with antigenic similarity to the native protein. J Gen Virol 76:3145–3152 [CrossRef]
    [Google Scholar]
  36. Rickinson A. B., Kieff E. 1996; Epstein-Barr virus. In Fields Virology , 3rd edn. pp  2397–2446 Edited by Fields B. N., Knipe D. M., Howley P. M. Philadelphia, PA: Lippincott-Raven;
    [Google Scholar]
  37. Roberge C. J., Larochelle B., Rola-Pleszczynski M., Gosselin J. 1997; Epstein–Barr virus induces GM-CSF synthesis by monocytes: effect on EBV-induced IL-1 and IL-1 receptor antagonist production in neutrophils. Virology 238:344–352 [CrossRef]
    [Google Scholar]
  38. Rooney C. M., Ng C. Y. C., Loftin S., Smith C. A., Li C., Krance R. A., Brenner M. K., Heslop H. E. 1995; Use of gene-modified virus-specific T lymphocytes to control Epstein-Barr-virus-related lymphoproliferation. Lancet 345:9–13 [CrossRef]
    [Google Scholar]
  39. Rubin D. I., Daube J. R. 1999; Subacute sensory neuropathy associated with Epstein-Barr virus. Muscle Nerve 22:1607–1610 [CrossRef]
    [Google Scholar]
  40. Savard M., Bélanger C., Tardif M., Gourde P., Flamand L., Gosselin J. 2000a; Infection of primary human monocytes by Epstein-Barr virus. J Virol 74:2612–2619 [CrossRef]
    [Google Scholar]
  41. Savard M., Bélanger C., Tremblay M. J., Dumais N., Flamand L., Borgeat P., Gosselin J. 2000b; EBV suppresses prostaglandin E2 biosynthesis in human monocytes. J Immunol 164:6467–6473 [CrossRef]
    [Google Scholar]
  42. Schneider-Schaulies S., Klagge I. M., ter Meulen V. 2003; Dendritic cells and measles virus infection. Curr Top Microbiol Immunol 276:77–101
    [Google Scholar]
  43. Scotet E., David-Ameline J., Peyrat M.-A. 9 other authors 1996; T cell response to Epstein-Barr virus transactivators in chronic rheumatoid arthritis. J Exp Med 184:1791–1800 [CrossRef]
    [Google Scholar]
  44. Sevilla N., Kunz S., McGavern D., Oldstone M. B. 2003; Infection of dendritic cells by lymphocytic choriomeningitis virus. Curr Top Microbiol Immunol 276:125–144
    [Google Scholar]
  45. Shimakage M., Kimura M., Yanoma S. 9 other authors 1999; Expression of latent and replicative-infection genes of Epstein-Barr virus in macrophage. Arch Virol 144:157–166 [CrossRef]
    [Google Scholar]
  46. Sixbey J. W., Nedrud J. G., Raab-Traub N., Hanes R. A., Pagano J. S. 1984; Epstein-Barr virus replication in oropharyngeal epithelial cells. N Engl J Med 310:1225–1230 [CrossRef]
    [Google Scholar]
  47. Spear P. G., Longnecker R. 2003; Herpesvirus entry: an update. J Virol 77:10179–10185 [CrossRef]
    [Google Scholar]
  48. Steinman R. M., Granelli-Piperno A., Pope M., Trumpfheller C., Ignatius R., Arrode G., Racz P., Tenner-Racz K. 2003; The interaction of immunodeficiency viruses with dendritic cells. Curr Top Microbiol Immunol 276:1–30
    [Google Scholar]
  49. Strnad B. C., Schuster T., Klein R., Hopkins R. F. III, Witmer T., Neubauer R. H., Rabin H. 1982; Production and characterization of monoclonal antibodies against the Epstein-Barr virus membrane antigen. J Virol 41:258–264
    [Google Scholar]
  50. Subklewe M., Paludan C., Tsang M. L., Mahnke K., Steinman R. M., Münz C. 2001; Dendritic cells cross-present latency gene products from Epstein-Barr virus-transformed B cells and expand tumor-reactive CD8+ killer T cells. J Exp Med 193:405–411 [CrossRef]
    [Google Scholar]
  51. Takeda T., Mizugaki Y., Matsubara L., Imai S., Koike T., Takada K. 2000; Lytic Epstein-Barr virus infection in the synovial tissue of patients with rheumatoid arthritis. Arthritis Rheum 43:1218–1225 [CrossRef]
    [Google Scholar]
  52. Tao Q., Srivastava G., Chan A. C., Chung L. P., Loke S. L., Ho F. C. 1995; Evidence for lytic infection by Epstein-Barr virus in mucosal lymphocytes instead of nasopharyngeal epithelial cells in normal individuals. J Med Virol 45:71–77 [CrossRef]
    [Google Scholar]
  53. Tardif M., Savard M., Flamand L., Gosselin J. 2002; Impaired protein kinase C activation/translocation in Epstein-Barr virus-infected monocytes. J Biol Chem 277:24148–24154 [CrossRef]
    [Google Scholar]
  54. Thorley-Lawson D. A., Miyashita E. M., Khan G. 1996; Epstein-Barr virus and the B cell: that's all it takes. Trends Microbiol 4:204–208 [CrossRef]
    [Google Scholar]
  55. Tugizov S. M., Berline J. W., Palefsky J. M. 2003; Epstein-Barr virus infection of polarized tongue and nasopharyngeal epithelial cells. Nat Med 9:307–314 [CrossRef]
    [Google Scholar]
  56. Walling D. M., Flaitz C. M., Hosein F. G., Montes-Walters M., Nichols C. M. 2004; Effect of Epstein-Barr virus replication on Langerhans cells in pathogenesis of oral hairy leukoplakia. J Infect Dis 189:1656–1663 [CrossRef]
    [Google Scholar]
  57. Wang X., Hutt-Fletcher L. M. 1998; Epstein-Barr virus lacking glycoprotein gp42 can bind to B cells but is not able to infect. J Virol 72:158–163
    [Google Scholar]
  58. Wang X., Kenyon W. J., Li Q., Müllberg J., Hutt-Fletcher L. M. 1998; Epstein-Barr virus uses different complexes of glycoproteins gH and gL to infect B lymphocytes and epithelial cells. J Virol 72:5552–5558
    [Google Scholar]
  59. Yaswen L. R., Stephens E. B., Davenport L. C., Hutt-Fletcher L. M. 1993; Epstein-Barr virus glycoprotein gp85 associates with the BKRF2 gene product and is incompletely processed as a recombinant protein. Virology 195:387–396 [CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.80140-0
Loading
/content/journal/jgv/10.1099/vir.0.80140-0
Loading

Data & Media loading...

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