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. 1995 Nov 1;182(5):1213–1221. doi: 10.1084/jem.182.5.1213

Infection of human endothelial cells with Epstein-Barr virus

PMCID: PMC2192185  PMID: 7595192

Abstract

Interleukin-6 (IL-6) promotes growth and tumorigenicity of Epstein-Barr virus (EBV)-immortalized B cells, and is abnormally elevated in the serum of solid organ transplant recipients who develop EBV-positive posttransplant lymphoproliferative disease (PTLD), but not in control transplant recipients. Endothelial cells derived from PTLD lesions were found to secrete spontaneously high levels of IL-6 in vitro for up to 4 mo. We examined possible mechanisms for sustained IL-6 production by endothelial cells. Here, we show that EBV can infect endothelial cells in vitro. After 3-4 wk incubation with lethally irradiated EBV- positive, but not EBV-negative cell lines, a proportion of human umbilical cord-derived endothelial cells (HUVECs) expressed in situ the EBV-encoded small RNAs (EBER). Southern blot analysis after polymerase chain reaction showed EBV DNA in HUVEC that had been incubated with lethally irradiated EBV-positive cells, but not in the controls. Exposure of HUVECs to lethally irradiated EBV-positive but not EBV- negative cell lines induced IL-6 production that was sustained for up to 120 d of culture. These studies identify endothelial cells as targets for EBV infection and raise the possibility that this infection may be important in the life cycle and pathology of EBV.

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Selected References

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  1. Brooks J. M., Murray R. J., Thomas W. A., Kurilla M. G., Rickinson A. B. Different HLA-B27 subtypes present the same immunodominant Epstein-Barr virus peptide. J Exp Med. 1993 Sep 1;178(3):879–887. doi: 10.1084/jem.178.3.879. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Burdin N., Péronne C., Banchereau J., Rousset F. Epstein-Barr virus transformation induces B lymphocytes to produce human interleukin 10. J Exp Med. 1993 Feb 1;177(2):295–304. doi: 10.1084/jem.177.2.295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Burrows S. R., Misko I. S., Sculley T. B., Schmidt C., Moss D. J. An Epstein-Barr virus-specific cytotoxic T-cell epitope present on A- and B-type transformants. J Virol. 1990 Aug;64(8):3974–3976. doi: 10.1128/jvi.64.8.3974-3976.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Burrows S. R., Sculley T. B., Misko I. S., Schmidt C., Moss D. J. An Epstein-Barr virus-specific cytotoxic T cell epitope in EBV nuclear antigen 3 (EBNA 3). J Exp Med. 1990 Jan 1;171(1):345–349. doi: 10.1084/jem.171.1.345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cen H., Williams P. A., McWilliams H. P., Breinig M. C., Ho M., McKnight J. L. Evidence for restricted Epstein-Barr virus latent gene expression and anti-EBNA antibody response in solid organ transplant recipients with posttransplant lymphoproliferative disorders. Blood. 1993 Mar 1;81(5):1393–1403. [PubMed] [Google Scholar]
  6. Deacon E. M., Pallesen G., Niedobitek G., Crocker J., Brooks L., Rickinson A. B., Young L. S. Epstein-Barr virus and Hodgkin's disease: transcriptional analysis of virus latency in the malignant cells. J Exp Med. 1993 Feb 1;177(2):339–349. doi: 10.1084/jem.177.2.339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fingeroth J. D., Weis J. J., Tedder T. F., Strominger J. L., Biro P. A., Fearon D. T. Epstein-Barr virus receptor of human B lymphocytes is the C3d receptor CR2. Proc Natl Acad Sci U S A. 1984 Jul;81(14):4510–4514. doi: 10.1073/pnas.81.14.4510. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gavioli R., Kurilla M. G., de Campos-Lima P. O., Wallace L. E., Dolcetti R., Murray R. J., Rickinson A. B., Masucci M. G. Multiple HLA A11-restricted cytotoxic T-lymphocyte epitopes of different immunogenicities in the Epstein-Barr virus-encoded nuclear antigen 4. J Virol. 1993 Mar;67(3):1572–1578. doi: 10.1128/jvi.67.3.1572-1578.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hart D. N., Baker B. W., Inglis M. J., Nimmo J. C., Starling G. C., Deacon E., Rowe M., Beard M. E. Epstein-Barr viral DNA in acute large granular lymphocyte (natural killer) leukemic cells. Blood. 1992 Apr 15;79(8):2116–2123. [PubMed] [Google Scholar]
  10. Howells G., Pham P., Taylor D., Foxwell B., Feldmann M. Interleukin 4 induces interleukin 6 production by endothelial cells: synergy with interferon-gamma. Eur J Immunol. 1991 Jan;21(1):97–101. doi: 10.1002/eji.1830210115. [DOI] [PubMed] [Google Scholar]
  11. Jirik F. R., Podor T. J., Hirano T., Kishimoto T., Loskutoff D. J., Carson D. A., Lotz M. Bacterial lipopolysaccharide and inflammatory mediators augment IL-6 secretion by human endothelial cells. J Immunol. 1989 Jan 1;142(1):144–147. [PubMed] [Google Scholar]
  12. Khanna R., Burrows S. R., Kurilla M. G., Jacob C. A., Misko I. S., Sculley T. B., Kieff E., Moss D. J. Localization of Epstein-Barr virus cytotoxic T cell epitopes using recombinant vaccinia: implications for vaccine development. J Exp Med. 1992 Jul 1;176(1):169–176. doi: 10.1084/jem.176.1.169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Lee E. S., Locker J., Nalesnik M., Reyes J., Jaffe R., Alashari M., Nour B., Tzakis A., Dickman P. S. The association of Epstein-Barr virus with smooth-muscle tumors occurring after organ transplantation. N Engl J Med. 1995 Jan 5;332(1):19–25. doi: 10.1056/NEJM199501053320104. [DOI] [PubMed] [Google Scholar]
  14. Lee S. P., Thomas W. A., Murray R. J., Khanim F., Kaur S., Young L. S., Rowe M., Kurilla M., Rickinson A. B. HLA A2.1-restricted cytotoxic T cells recognizing a range of Epstein-Barr virus isolates through a defined epitope in latent membrane protein LMP2. J Virol. 1993 Dec;67(12):7428–7435. doi: 10.1128/jvi.67.12.7428-7435.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lindhout E., Lakeman A., Mevissen M. L., de Groot C. Functionally active Epstein-Barr virus-transformed follicular dendritic cell-like cell lines. J Exp Med. 1994 Apr 1;179(4):1173–1184. doi: 10.1084/jem.179.4.1173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Masucci M. G., Ernberg I. Epstein-Barr virus: adaptation to a life within the immune system. Trends Microbiol. 1994 Apr;2(4):125–130. doi: 10.1016/0966-842x(94)90599-1. [DOI] [PubMed] [Google Scholar]
  17. McClain K. L., Leach C. T., Jenson H. B., Joshi V. V., Pollock B. H., Parmley R. T., DiCarlo F. J., Chadwick E. G., Murphy S. B. Association of Epstein-Barr virus with leiomyosarcomas in children with AIDS. N Engl J Med. 1995 Jan 5;332(1):12–18. doi: 10.1056/NEJM199501053320103. [DOI] [PubMed] [Google Scholar]
  18. Qu L., Rowe D. T. Epstein-Barr virus latent gene expression in uncultured peripheral blood lymphocytes. J Virol. 1992 Jun;66(6):3715–3724. doi: 10.1128/jvi.66.6.3715-3724.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Rickinson A. B., Moss D. J., Wallace L. E., Rowe M., Misko I. S., Epstein M. A., Pope J. H. Long-term T-cell-mediated immunity to Epstein-Barr virus. Cancer Res. 1981 Nov;41(11 Pt 1):4216–4221. [PubMed] [Google Scholar]
  20. Riddler S. A., Breinig M. C., McKnight J. L. Increased levels of circulating Epstein-Barr virus (EBV)-infected lymphocytes and decreased EBV nuclear antigen antibody responses are associated with the development of posttransplant lymphoproliferative disease in solid-organ transplant recipients. Blood. 1994 Aug 1;84(3):972–984. [PubMed] [Google Scholar]
  21. Scala G., Quinto I., Ruocco M. R., Arcucci A., Mallardo M., Caretto P., Forni G., Venuta S. Expression of an exogenous interleukin 6 gene in human Epstein Barr virus B cells confers growth advantage and in vivo tumorigenicity. J Exp Med. 1990 Jul 1;172(1):61–68. doi: 10.1084/jem.172.1.61. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Sironi M., Muñoz C., Pollicino T., Siboni A., Sciacca F. L., Bernasconi S., Vecchi A., Colotta F., Mantovani A. Divergent effects of interleukin-10 on cytokine production by mononuclear phagocytes and endothelial cells. Eur J Immunol. 1993 Oct;23(10):2692–2695. doi: 10.1002/eji.1830231046. [DOI] [PubMed] [Google Scholar]
  23. Straus S. E., Cohen J. I., Tosato G., Meier J. NIH conference. Epstein-Barr virus infections: biology, pathogenesis, and management. Ann Intern Med. 1993 Jan 1;118(1):45–58. doi: 10.7326/0003-4819-118-1-199301010-00009. [DOI] [PubMed] [Google Scholar]
  24. Su I. J., Hsieh H. C., Lin K. H., Uen W. C., Kao C. L., Chen C. J., Cheng A. L., Kadin M. E., Chen J. Y. Aggressive peripheral T-cell lymphomas containing Epstein-Barr viral DNA: a clinicopathologic and molecular analysis. Blood. 1991 Feb 15;77(4):799–808. [PubMed] [Google Scholar]
  25. Suzushima H., Matsushita S., Nakamura R., Nishimura S., Okubo T., Asou N., Kawa-Ha K., Hirai K., Takatsuki K. Detection of Epstein-Barr viral DNA in aggressive CD8+ T cell leukaemic cells. Br J Haematol. 1992 Dec;82(4):774–776. doi: 10.1111/j.1365-2141.1992.tb06960.x. [DOI] [PubMed] [Google Scholar]
  26. Taga K., Tosato G. IL-10 inhibits human T cell proliferation and IL-2 production. J Immunol. 1992 Feb 15;148(4):1143–1148. [PubMed] [Google Scholar]
  27. Tanner J., Tosato G. Impairment of natural killer functions by interleukin 6 increases lymphoblastoid cell tumorigenicity in athymic mice. J Clin Invest. 1991 Jul;88(1):239–247. doi: 10.1172/JCI115283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Thomas J. A., Allday M. J., Crawford D. H. Epstein-Barr virus-associated lymphoproliferative disorders in immunocompromised individuals. Adv Cancer Res. 1991;57:329–380. doi: 10.1016/s0065-230x(08)61003-9. [DOI] [PubMed] [Google Scholar]
  29. Tierney R. J., Steven N., Young L. S., Rickinson A. B. Epstein-Barr virus latency in blood mononuclear cells: analysis of viral gene transcription during primary infection and in the carrier state. J Virol. 1994 Nov;68(11):7374–7385. doi: 10.1128/jvi.68.11.7374-7385.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Timens W., Boes A., Vos H., Poppema S. Tissue distribution of the C3d/EBV-receptor: CD21 monoclonal antibodies reactive with a variety of epithelial cells, medullary thymocytes, and peripheral T-cells. Histochemistry. 1991;95(6):605–611. doi: 10.1007/BF00266748. [DOI] [PubMed] [Google Scholar]
  31. Tosato G., Jones K., Breinig M. K., McWilliams H. P., McKnight J. L. Interleukin-6 production in posttransplant lymphoproliferative disease. J Clin Invest. 1993 Jun;91(6):2806–2814. doi: 10.1172/JCI116523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Tosato G., Seamon K. B., Goldman N. D., Sehgal P. B., May L. T., Washington G. C., Jones K. D., Pike S. E. Monocyte-derived human B-cell growth factor identified as interferon-beta 2 (BSF-2, IL-6). Science. 1988 Jan 29;239(4839):502–504. doi: 10.1126/science.2829354. [DOI] [PubMed] [Google Scholar]
  33. Tosato G., Steinberg A. D., Yarchoan R., Heilman C. A., Pike S. E., De Seau V., Blaese R. M. Abnormally elevated frequency of Epstein-Barr virus-infected B cells in the blood of patients with rheumatoid arthritis. J Clin Invest. 1984 Jun;73(6):1789–1795. doi: 10.1172/JCI111388. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Tosato G., Tanner J., Jones K. D., Revel M., Pike S. E. Identification of interleukin-6 as an autocrine growth factor for Epstein-Barr virus-immortalized B cells. J Virol. 1990 Jun;64(6):3033–3041. doi: 10.1128/jvi.64.6.3033-3041.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Vieira P., de Waal-Malefyt R., Dang M. N., Johnson K. E., Kastelein R., Fiorentino D. F., deVries J. E., Roncarolo M. G., Mosmann T. R., Moore K. W. Isolation and expression of human cytokine synthesis inhibitory factor cDNA clones: homology to Epstein-Barr virus open reading frame BCRFI. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1172–1176. doi: 10.1073/pnas.88.4.1172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Williamson B. D., Carswell E. A., Rubin B. Y., Prendergast J. S., Old L. J. Human tumor necrosis factor produced by human B-cell lines: synergistic cytotoxic interaction with human interferon. Proc Natl Acad Sci U S A. 1983 Sep;80(17):5397–5401. doi: 10.1073/pnas.80.17.5397. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Wu T. C., Mann R. B., Charache P., Hayward S. D., Staal S., Lambe B. C., Ambinder R. F. Detection of EBV gene expression in Reed-Sternberg cells of Hodgkin's disease. Int J Cancer. 1990 Nov 15;46(5):801–804. doi: 10.1002/ijc.2910460509. [DOI] [PubMed] [Google Scholar]
  38. de Campos-Lima P. O., Levitsky V., Brooks J., Lee S. P., Hu L. F., Rickinson A. B., Masucci M. G. T cell responses and virus evolution: loss of HLA A11-restricted CTL epitopes in Epstein-Barr virus isolates from highly A11-positive populations by selective mutation of anchor residues. J Exp Med. 1994 Apr 1;179(4):1297–1305. doi: 10.1084/jem.179.4.1297. [DOI] [PMC free article] [PubMed] [Google Scholar]

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