Chapter 5 : Pathogenesis of Epstein-Barr Virus

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Epstein-Barr virus (EBV) is a human DNA tumor virus with an extraordinarily diverse oncogenic potential. No other virus, human or otherwise, has shown the ability to contribute to malignant transformation in such a variety of cell backgrounds. Studies of EBV related malignancies in immunodeficiency states (posttransplant and AIDS) have provided insight into the significance in vivo of EBV-specific T-cell immunity, which has been studied so elegantly in vitro, in controlling primary and persistent EBV infection. Recent studies on tumor tissue from the EBV diseases have suggested that viral signaling, especially through the LMP1 protein, may directly contribute to the development and maintenance of the malignant phenotype. Novel strategies aimed at restoring antiviral T-cell immunity have shown promise in the postbone marrow transplant setting in controlling EBV-related lymphoproliferations. Future effort into better characterizing the role of EBV in T-lymphocyte malignancies and in non-lymphoid malignancies (Nasopharyngeal carcinoma (NPC) and smooth muscle tumors) will likely identify new pathogenic mechanisms utilized by this versatile virus that have yet to be appreciated in the better-studied EBV-related B-lymphoproliferative diseases.

Citation: Liebowitz D. 1998. Pathogenesis of Epstein-Barr Virus, p 175-199. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch5
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Figure 1

A model for the virus and cellular interactions that occur in primary EBV infection, persistence, and reactivation. Acute (primary [1°]) infection occurs in the oropharyngeal epithelium, and viral replication ensues. B lymphocytes are subsequently infected and display a latency type III viral gene expression pattern. At this point, the expanding population of EBV-infected B lymphoblasts are controlled by a primary CTL and NK cell response. EBV persistence is largely maintained in infected B cells that display a latency type I viral gene expression pattern. These cells may reactivate to a latency type II viral gene expression pattern, which is controlled by a secondary (memory) CTL response, or may be induced into lytic replication, where progeny virus may reinfect normal target tissues such as squamous epithelium and uninfected B lymphocytes. Details of the EBNA proteins and latent states are found in the text and in chapter 4.

Citation: Liebowitz D. 1998. Pathogenesis of Epstein-Barr Virus, p 175-199. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch5
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Figure 2

A model for the progression of typical EBV-positive B-cell PTLD from “early” proliferative lesions to polymorphic PTLD and then to monomorphic PTLD, based on viral gene expression and cytogenetic data. Polymorphic lesions are usually polyclonal or oligoclonal, display a latency type III viral gene expression pattern, and do not have any cytogenetic evidence for cellular oncogene activation. Monomorphic lesions are monoclonal, also have a latency type III viral gene expression pattern, and frequently have recurring cytogenetic abnormalities. Moreover, the histologic subtype of the monomorphic lesions correlates with specific recurring cytogenetic abnormalities: approximately 70% of the monomorphic B-cell lesions had diffuse large-cell, immunoblastic (DLC-IB) histology and frequently had +11, +9, or 3q27 () recurring abnormalities; approximately 20% of the monomorphic B-cell lesions had small, non-cleaved, Burkitt-like (SNC-BL) histology and always had the t(8;14) or t(8;22) translocations involving ; 10% of the monomorphic B-cell lesions had diffuse large-cell, centroblastic (DLC-CB) histology and did not have recurring abnormalities. The continued expression of EBV proteins, such as the LMP1 transforming gene in the monomorphic PTLD lesions, suggests that these proteins play an important role in the progression and maintenance of the transformed phenotype. The association of specific recurring abnormalities with different monomorphic histologic subtypes indicates that cellular genetic features may ultimately determine the phenotype of monomorphic lesions.

Citation: Liebowitz D. 1998. Pathogenesis of Epstein-Barr Virus, p 175-199. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch5
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1. Anagnostopoulos, I.,, H. Herbst,, G. Niedobitek,, and H. Stein. 1989. Demonstration of monoclonal EBV genomes in Hodgkin's disease and Ki-1-positive anaplastic large cell lymphoma by combined Southern blot and in situ hybridization [see comments]. Blood 74: 810 816.
2. Armstrong, R. W.,, M. J. Armstrong,, M. C. Yu,, and B. E. Henderson. 1983. Salted fish and inhalants as risk factors for nasopharyngeal carcinoma in Malaysian Chinese. Cancer Res. 43: 2967 2970.
3. Baichwal, V. R.,, and B. Sugden. 1988. Transformation of Balb 3T3 cells by the BNLF-1 gene of Epstein-Barr virus. Oncogene 2: 461 467.
4. Blanche, S.,, F. Le Deist,, F. Veber,, G. Lenoir,, A. M. Fischer,, J. Brochier,, C. Boucheix,, M. Delaage,, C. Grisceill,, and A. Fischer. 1988. Treatment of severe Epstein-Barr virus-induced polyclonal B-lymphocyte proliferation by anti-B-cell monoclonal antibodies. Two cases after HLA-mismatched bone marrow transplantation Ann. Intern. Med. 108: 199 203.
5. Brooks, L.,, Q. Y. Yao,, A. B. Rickinson,, and L. S. Young. 1992. Epstein-Barr virus latent gene transcription in nasopharyngeal carcinoma cells: coexpression of EBNA1, LMP1, and LMP2 transcripts. J. Virol. 66: 2689 2697.
6. Brousset, P.,, S. Chittal,, D. Schlaifer,, J. Icart,, C. Payen,, F. Rigal Huguet,, J. J. Voigt,, and G. Deisol. 1991. Detection of Epstein-Barr virus messenger RNA in Reed-Sternberg cells of Hodgkin's disease by in situ hybridization with biotinylated probes on specially processed modified acetone methyl benzoate xylene (ModAMeX) sections [see comments]. Blood 77: 1781 1786.
7. Brown, N. A.,, C. R. Liu,, Y. F. Wang,, and C. R. Garcia. 1988. B-cell lymphoproliferation and lymphomagenesis are associated with clonotypic intracellular terminal regions of the Epstein-Barr virus. J. Virol. 62: 962 969.
8. Burkitt, D. P. 1958. A sarcoma involving the jaws in African children. Br. J. Surg. 46: 218 223.
9. Burkitt, D. P. 1962. A children's cancer dependent on climactic factors. Nature 194: 232 234.
10. Burkitt, D. P. 1962. Determining the climactic limitations of a children's cancer common in Africa. Br. Med. J. 2: 1019 1023.
11. Busson, P.,, R. McCoy,, R. Sadler,, K. Gilligan,, T. Tursz,, and N. Raab Traub. 1992. Consistent transcription of the Epstein-Barr virus LMP2 gene in nasopharyngeal carcinoma. J. Virol. 66: 3257 3262.
12. Cannon, M. J.,, P. Pisa,, R. I. Fox,, and N. R. Cooper. 1990. Epstein-Barr virus induces aggressive lymphoproliferative disorders of human B cell origin in SCID/hu chimeric mice. J. Clin. Invest. 85: 1333 1337.
13. Carbone, A.,, G. Gaidano,, A. Gloghini,, C. Pastore,, G. Saglio,, U. Tirelli,, R. Dalla Favera,, and B. Falini. 1997. BCL-6 protein expression in AIDS-related non-Hodgkin's lymphomas: inverse relationship with Epstein-Barr virus-encoded latent membrane protein-1 expression. Am. J. Pathol. 150: 155 165.
14. Chen, C. L.,, R. H. Sadler,, D. M. Walling,, I. J. Su,, H. C. Hsieh,, and N. Raab Traub. 1993. Epstein-Barr virus (EBV) gene expression in EBV-positive peripheral T-cell lymphomas. J. Virol. 67: 6303 6308.
15. Cleary, M. L.,, M. A. Epstein,, S. Finerty,, R. F. Dorfman,, G. W. Bornkamm,, J. K. Kirkwood,, A. J. Morgan,, and J. Sklar. 1985. Individual tumors of multifocal EB virus-induced malignant lymphomas in tamarins arise from different B-cell clones. Science 228: 722 724.
16. Cohen, J. I. 1991. Epstein-Barr virus lymphoproliferative disease associated with acquired immunodeficiency. Medicine (Baltimore) 70: 137 160.
17. Dalla-Favera, R.,, M. Bregni,, J. Erikson,, D. Patterson,, R. C. Gallo,, and C. M. Croce. 1982. Human c myc oncogene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells. Proc. Natl. Acad. Sci. USA 79: 7824 7827.
18. Devergne, O.,, E. Hatzivassiliou,, K. M. Izumi,, K. M. Kaye,, M. F. Kleijnen,, E. Kieff,, and G. Mosallos. 1996. Association of TRAF1, TRAF2, and TRAF3 with an Epstein-Barr virus LMP1 domain important for B-lymphocyte transformation: role in NF-κB activation. Mol. Cell. Biol. 16: 7098 7108.
19. Ende, M.,, and F. I. Ende. 1994. Correction of X-linked lymphoproliferative disease by stem-cell transplantation [ letter; comment]. N. Engl. J. Med. 330: 1159.
20. Epstein, M. A.,, B. Achong,, and Y. Barr. 1964. Virus particles in cultured lymphoblasts from Burkitt's lymphoma. Lancet 1: 702 703.
21. Ernberg, I.,, and J. Andersson. 1986. Acyclovir efficiently inhibits oropharyngeal excretion of Epstein-Barr virus in patients with acute infectious mononucleosis. J. Gen. Virol. 67: 2267 2272.
22. Fahraeus, R.,, H. L. Fu,, I. Ernberg,, J. Finke,, M. Rowe,, G. Klein,, K. Falk,, E. Nilsson,, M. Yadav,, P. Busson,, T. Tursz,, and B. Kallin. 1988. Expression of Epstein-Barr virus-encoded proteins in nasopharyngeal carcinoma. Int. J. Cancer 42: 329 338.
23. Fischer, A.,, S. Blanche,, J. Le Bidois,, P. Bordigoni,, J. L. Gamier,, P. Nlaudet,, F. Morinet,, F. Le Deist,, A. M. Fischer,, C. Griscelli,, and M. Hirn. 1991. Anti-B-cell monoclonal antibodies in the treatment of severe B-cell lymphoproliferative syndrome following bone marrow and organ transplantation. N. Engl. J. Med. 324: 1451 1456.
24. Gaidano, G.,, F. Lo Coco,, B. H. Ye,, D. Shibata,, A. M. Levine,, D. M. Knowles,, and R. Dalla Favera. 1994. Rearrangements of the BCL-6 gene in acquired immunodeficiency syndrome-associated non-Hodgkin's lymphoma: association with diffuse large-cell subtype. Blood 84: 397 402.
25. Garner, J. G.,, M. S. Hirsch,, and R. T. Schooley. 1984. Prevention of Epstein-Barr virus-induced B-cell outgrowth by interferon alpha. Infect. Immun. 43: 920 924.
26. Geser, A.,, G. M. Lenoir,, M. Anvret,, G. Bornkamm,, G. Klein,, E. H. Williams,, D. H. Wright,, and G. De The. 1983. Epstein-Barr virus markers in a series of Burkitt's lymphomas from the West Nile District, Uganda. Eur. J. Cancer Clin. Oncol. 19: 1393 1404.
27. Gilligan, K.,, H. Sato,, P. Rajadurai,, P. Busson,, L. Young,, A. Rickinson,, T. Tursz,, and N. Raab Traub. 1990. Novel transcription from the Epstein-Barr virus terminal EcoRI fragment, DIJhet, in a nasopharyngeal carcinoma. J. Virol. 64: 4948 4956.
28. Gratama, J. W.,, M. M. Zutter,, J. Minarovits,, M. A. Oosterveer,, E. D. Thomas,, G. Klein,, and I. Ernberg. 1991. Expression of Epstein-Barr virus-encoded growth-transformation-associated proteins in lymphoproliferations of bone-marrow transplant recipients. Int. J. Cancer 47: 188 192.
29. Greenspan, D.,, Y. G. De Souza,, M. A. Conant,, H. Hollander,, S. K. Chapman,, E. T. Lennette,, V. Petersen,, and J. S. Greenspan. 1990. Efficacy of desciclovir in the treatment of Epstein-Barr virus infection in oral hairy leukoplakia. J. Acquired Immune Defic. Syndr. 3: 571 578.
30. Greenspan, D.,, J. S. Greenspan,, Y. de Souza,, J. A. Levy,, and A. M. Ungar. 1989. Oral hairy leukoplakia in an HIV-negative renal transplant recipient. J. Oral Pathol. Med. 18: 32 34.
31. Greenspan, J. S.,, and D. Greenspan. 1989. Oral hairy leukoplakia: diagnosis and management. Oral Surg. Oral Med. Oral Pathol. 67: 396 403.
32. Greenspan, J. S.,, D. Greenspan,, E. T. Lennette,, D. I. Abrams,, M. A. Conant,, V. Petersen,, and U. K. Freese. 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.
33. Gregory, C. D.,, C. Dive,, S. Henderson,, C. A. Smith,, G. T. Williams,, J. Gordon,, and A. B. Rickinson. 1991. Activation of Epstein-Barr virus latent genes protects human B cells from death by apoptosis. Nature 349: 612 614.
34. Gregory, C. D.,, R. J. Murray,, C. F. Edwards,, and A. B. Rickinson. 1988. Downregulation of cell adhesion molecules LFA-3 and ICAM-1 in Epstein-Barr virus-positive Burkitt's lymphoma underlies tumor cell escape from virus-specific T cell surveillance. J. Exp. Med. 167: 1811 1824.
35. Gregory, C. D.,, M. Rowe,, and A. B. Rickinson. 1990. Different Epstein-Barr virus-B cell interactions in phenotypically distinct clones of a Burkitt's lymphoma cell line. J. Gen. Virol. 71: 1481 1495.
36. Gross, T. G.,, A. H. Filipovich,, M. E. Conley,, E. Pracher,, K. Schmiegelow,, J. D. Verdirame,, M. Vowels,, L. L. Williams,, and T. A. Seemayer. 1996. Cure of X-linked lymphoproliferative disease (XLP) with allogeneic hematopoietic stem cell transplantation (HSCT): report from the XLP registry. Bone Marrow Transplant. 17: 741 744.
37. Hamilton Dutoit, S. J.,, G. Pallesen,, M. B. Franzmann,, J. Karkov,, F. Black,, P. Skinhoj,, and C. Pedersen. 1991. AIDS-related lymphoma. Histopathology, immunophenotype, and association with Epstein-Barr virus as demonstrated by in situ nucleic acid hybridization. Am. J. Pathol. 138: 149 163.
38. Hatzubai, A.,, M. Anafi,, M. G. Masucci,, J. Dillner,, R. A. Lerner,, G. Klein,, and D. Sulitzeanu. 1987. Down-regulation of the EBV-encoded membrane protein (LMP) in Burkitt lymphomas. Int. J. Cancer 40: 358 364.
39. Henderson, S.,, M. Rowe,, C. Gregory,, D. Croom Carter,, F. Wang,, R. Longnecker,, E. Kieff,, and A. Rickinson. 1991. Induction of bcl-2 expression by Epstein-Barr virus latent membrane protein 1 protects infected B cells from programmed cell death. Cell 65: 1107 1115.
40. Henle, G.,, and W. Henle. 1970. Observations on childhood infections with the Epstein-Barr virus. J. Infect. Dis. 121: 303 310.
41. Henle, G.,, and W. Henle. 1976. Epstein-Barr virus-specific IgA serum antibodies as an outstanding feature of nasopharyngeal carcinoma. Int. J. Cancer 17: 1 7.
42. Henle, G.,, W. Henle,, and V. Diehl. 1968. Relation of Burkitt's tumour associated herpes-type virus to infectious mononucleosis. Proc. Natl. Acad. Sci. USA 59: 94 101.
43. Henle, W.,, V. Diehl,, G. Kohn,, H. zur Hausen,, and G. Henle. 1967. Herpes-type virus and chromosome marker in normal leukocytes after growth with irradiated Burkitt cells. Science 157: 1064 1065.
44. Herbst, H.,, F. Dallenbach,, M. Hummel,, G. Niedobitek,, S. Piled,, N. Muller Lantzsch,, and H. Stein. 1991. Epstein-Barr virus latent membrane protein expression in Hodgkin and Reed-Sternberg cells. Proc. Natl. Acad. Sci. USA 88: 4766 4770.
45. Heslop, H. E.,, C. Y. Ng,, C. Li,, C. A. Smith,, S. K. Loftin,, R. A. Krance,, M. K. Brenner,, and C. M. Rooney. 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.
46. Ho, J. 1978. An epidemiologic and clinical study of nasopharyngeal carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 4: 183 197.
47. Ho, M.,, R. Jaffe,, G. Miller,, M. K. Breinig,, J. S. Dummer,, L. Makowka,, R. W. Atchison,, F. Karrer,, M. A. Nalesnik,, and T. E. Starzl. 1988. The frequency of Epstein-Barr virus infection and associated lymphoproliferative syndrome after transplantation and its manifestations in children. Transplantation 45: 719 727.
48. Ho, M.,, G. Miller,, R. W. Atchison,, M. K. Breinig,, J. S. Dummer,, W. Andiman,, T. E. Starzl,, R. Eastman,, B. P. Griffith,, R. L. Hardesty,, H. T. Bahnson,, T. R. Hakala,, and J. T. Rosenthal. 1985. Epstein-Barr virus infections and DNA hybridization studies in posttransplantation lymphoma and lymphoproliferative lesions: the role of primary infection. J. Infect. Dis. 152: 876 886.
49. Huang, D. P.,, J. H. C. Ho,, W. K. Chan,, W. H. Lau,, and M. Lui. 1989. Cytogenetics of undifferentiated nasopharyngeal carcinoma xenografts from southern Chinese. Int. J. Cancer 43: 936 839.
50. Huang, D. P.,, J. H. C. Ho,, W. Henle,, and G. Henle. 1974. Demonstration of Epstein-Barr virus associated nuclear antigen in nasopharyngeal carcinoma cells from fresh biopsies. Int. J. Cancer 14: 580 588.
51. Huang, D. P.,, K. W. Lo,, P. H. Choi,, A. Y. Ng,, S. Y. Tsao,, G. K. Yiu,, and J. C. Lee. 1991. Loss of heterozygosity on the short arm of chromosome 3 in nasopharyngeal carcinoma. Cancer Genet. Cytogenet. 54: 91 99.
52. Huen, D.,, S. Henderson,, D. Croom-Carter,, and M. Rowe. 1995. The Epstein-Barr virus latent membrane protein-1 (LMP1) mediates activation of NF-kappa B and cell surface phenotype via two effector regions in its carboxy-terminal cytoplasmic domain. Oncogene 10: 549 560.
53. Johansson, B.,, G. Klein,, W. Henle,, and G. Henle. 1970. Epstein-Barr virus (EBV)-associated antibody patterns in lymphoma and leukemia. Int. J. Cancer 6: 450 62.
54. Kafuko, G. W.,, and D. P. Burkitt. 1970. Burkitt's lymphoma and malaria. Int. J. Cancer 6: 1 9.
55. Kaye, K. M.,, O. Devergne,, J. N. Harada,, K. M. Izumi,, R. Yalamanchili,, E. Kieff,, and G. Mosalios. 1996. Tumor necrosis family receptor associated factor 2 is a mediator of NF-κB activation by latent infection membrane protein 1, the Epstein-Barr virus fransforming protein. Proc. Natl. Acad. Sci. USA 93: 11085 11090.
56. Kaye, K. M.,, K. M. Izumi,, and E. Kieff. 1993. Epstein-Barr virus latent membrane protein 1 is essential for B-lymphocyte growth transformation. Proc. Natl. Acad. Sci. USA 90: 9150 9154.
57. Khanna, R.,, S. R. Burrows,, M. G. Kurilla,, C. A. Jacob,, I. S. Misko,, T. B. Sculley,, E. Kieff,, and D. J. Moss. 1992. Localization of Epstein-Barr virus cytotoxic T cell epitopes using recombinant vaccinia: implications for vaccine development. J. Exp. Med. 176: 169 176.
58. Kieff, E., 1996. Epstein-Barr virus and its replication, p. 2343 2396. In B. N. Fields,, D. M. Knipe,, and P. M. Howley (ed.), Fields Virology, 3rd ed., vol. 2. Lippincott-Raven, Philadelphia.
59. Klein, G.,, B. C. Giovanella,, T. Lindahl,, P. J. Fialkow,, S. Singh,, and J. S. Steihlin. 1974. Direct evidence for the presence of Epstein-Barr virus DNA and nuclear antigen in malignant epithelial cells from patients with poorly differentiated carcinoma of the nasopharynx. Proc. Natl. Acad. Sci. USA 71: 4737 4741.
60. Knowles, D. M.,, E. Cesarman,, A. Chadburn,, G. Frizzera,, J. Chen,, E. A. Rose,, and R. E. Michler. 1995. Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of posttransplantation lymphoproliferative disorders. Blood 85: 552 565.
61. Lanyi, A.,, B. Li,, S. Li,, C. B. Talmadge,, B. Brichacek,, J. R. Davis,, B. A. Kozel,, B. Trask,, G. van den Engh,, E. Uzvolgyi,, E. J. Stanbridge,, D. L. Nelson,, C. Chinault,, H. Heslop,, T. G. Gross,, T. A. Seemayer,, G. Klein,, D. T. Purtllo,, and J. Sumegi. 1997. A yeast artificial chromosome (YAC) contig encompassing the critical region of the X-linked lymphoproliferative disease (XLP) locus. Genomics 39: 55 65.
62. Leder, P.,, J. Battey,, G. Lenoir,, C. Moulding,, W. Murphy,, H. Potter,, T. Stewart,, and R. Taub. 1983. Translocations among antibody genes in human cancer. Science 222: 765 771.
63. Levine, A. M. 1987. Non-Hodgkin's lymphomas and other malignancies in the acquired immune deficiency syndrome. Semin. Oncol. 14: 34 39.
64. Liebowitz, D.,, and E. Kieff. 1989. Epstein-Barr virus latent membrane protein: induction of B-cell activation antigens and membrane patch formation does not require vimentin. J. Virol. 63: 4051 4054.
65. Liebowitz, D.,, M. M. LeBeau,, and O. I. Olopade. 1997. Evidence for signal transduction through the TNF receptor pathway in post-transplant lymphoproliferative disorders. J. Acquired Immune Defic. Syndr. Hum. Retrovirol. 14: A51.
66. Liebowitz, D.,, J. Mannick,, K. Takada,, and E. Kieff. 1992. Phenotypes of Epstein-Barr virus LMP1 deletion mutants indicate transmembrane and ammo-terminal cytoplasmic domains necessary for effects in B-lymphoma cells. J. Virol. 66: 4612 4616.
67. Lombardi, L.,, E. W. Newcomb,, and R. Dalla Favera. 1987. Pathogenesis of Burkitt lymphoma: expression of an activated c-myc oncogene causes the tumorigenic conversion of EBV-infected human B lymphoblasts. Cell 49: 161 170.
68. MacMahon, E. M.,, J. D. Glass,, S. D. Hayward,, R. B. Mann,, P. S. Becker,, P. Charache,, J. C. McArthur,, and R. F. Ambinder. 1991. Epstein-Barr virus in AIDS-related primary central nervous system lymphoma. Lancet 338: 969 973.
69. MacMahon, E. M.,, J. D. Glass,, S. D. Hayward,, R. B. Mann,, P. Charache,, J. C. McArthur,, and R. F. Ambinder. 1992. Association of Epstein-Barr virus with primary central nervous system lymphoma in AIDS. AIDS Res. Hum. Retroviruses 8: 740 742.
70. Manilov, G.,, and Y. Manilova. 1972. Marker band in one chromosome 14 from Burkitt lymphomas. Nature 237: 33 34.
71. Manilov, G.,, Y. Manilova,, G. Klein,, G. Lenoir,, and A. Levan. 1986. Alternative involvement of two cytogenetically distinguishable breakpoints on chromosome 8 in Burkitt's lymphoma associated translocations. Cancer Genet. Cytogenet. 20: 95 99.
72. Minarovits, J.,, L. F. Hu,, S. Imai,, Y. Harabuchi,, A. Kataura,, S. Minarovits Kormuta,, T. Osato,, and G. Klein. 1994. Clonality, expression and methylation patterns of the Epstein-Barr virus genomes in lethal midline granulomas classified as peripheral angiocentric T cell lymphomas. J. Gen. Virol. 75: 77 84.
73. Mitchell, T.,, and B. Sugden. 1995. Stimulation of NF-kappa B-mediated transcription by mutant derivatives of the latent membrane protein of Epstein-Barr virus. J. Virol. 69: 2968 2976.
74. Moghaddam, A.,, M. Rosenzweig,, D. Lee Parritz,, B. Annis,, R. P. Johnson,, and F. Wang. 1997. An animal model for acute and persistent Epstein-Barr virus infection. Science 276: 2030 2033.
75. Morgan, A. J.,, S. Finerty,, K. Lovgren,, F. T. Scullion,, and B. Morein. 1988. Prevention of Epstein-Barr (EB) virus-induced lymphoma in cottontop tamarins by vaccination with the EB virus envelope glycoprotein gp340 incorporated into immune-stimulating complexes. J. Gen. Virol. 69: 2093 2096.
76. Morgan, A. J.,, M. Mackett,, S. Finerty,, J. R. Arrand,, F. T. Scullion,, and M. A. Epstein. 1988. Recombinant vaccinia virus expressing Epstein-Barr virus glycoprotein gp340 protects cottontop tamarins against EB virus-induced malignant lymphomas. J. Med. Virol. 25: 189 195.
77. Moslalos, G.,, M. Birkenbach,, R. Yatamanchili,, T. VanArsdale,, C. Ware,, and E. Kieff. 1995. The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell 80: 389 399.
78. Mosier, D. E.,, R. J. Gulizia,, S. M. Baird,, and D. B. Wilson. 1988. Transfer of a functional human immune system to mice with severe combined immunodeficiency. Nature 335: 256 259.
79. Mosier, D. E.,, G. R. Picchio,, S. M. Baird,, R. Kobayashi,, and T. J. Kipps. 1992. Epstein-Barr virus-induced human B-cell lymphomas in SCID mice reconstituted with human peripheral blood leukocytes. Cancer Res. 52: 5552s 5553s.
80. Mosier, D. E.,, G. R. Picchio,, M. B. Kirven,, J. L. Gamier,, B. E. Torbett,, S. M. Baird,, R. Kobayashi,, and T. J. Kipps. 1992. EBV-induced human B cell lymphomas in hu-PBL-SCID mice. AIDS Res. Hum. Retroviruses 8: 735 740.
81. Moss, D. J.,, S. R. Burrows,, R. Khanna,, I. S. Misko,, and T. B. Sculley. 1992. Immune surveillance against Epstein-Barr virus. Semin. Immunol. 4: 97 104.
82. Moss, D. J.,, A. B. Rickinson,, and J. H. Pope. 1978. Long-term T-cell-mediated immunity to Epstein-Barr virus in man. I. Complete regression of virus-induced transformation in cultures of seropositive donor leukocytes. Int. J. Cancer 22: 662 668.
83. Mueller, N. 1987. Epidemiologic studies assessing the role of the Epstein-Barr virus in Hodgkin's disease. Yale J. Biol. Med. 60: 321 332.
84. Mueller, N.,, A. Evans,, N. L. Harris,, G. W. Comstock,, E. Jellum,, K. Magnus,, N. Orentreich,, B. F. Polk,, and J. Vogelman. 1989. Hodgkin's disease and Epstein-Barr virus. Altered antibody pattern before diagnosis. N. Engl. J. Med. 320: 689 695.
85. Murray, R. J.,, M. G. Kurilla,, J. M. Brooks,, W. A. Thomas,, M. Rowe,, E. Kieff,, and A. B. Rickinson. 1992. Identification of target antigens for the human cytotoxic T cell response to Epstein-Barr virus (EBV): implications for the immune control of EBV-positive malignancies. J. Exp. Med. 176: 157 168.
86. Murray, R. J.,, D. Wang,, L. S. Young,, F. Wang,, M. Rowe,, E. Kieff,, and A. B. Rickinson. 1988. Epstein-Barr virus-specific cytotoxic T-cell recognition of transfectants expressing the virus-coded latent membrane protein LMP. J. Virol. 62: 3747 3755.
87. Murray, R. J.,, L. S. Young,, A. Calender,, C. D. Gregory,, M. Rowe,, G. M. Lenoir,, and A. B. Rickinson. 1988. Different patterns of Epstein-Barr virus gene expression and of cytotoxic T-cell recognition in B-cell lines infected with transforming (B95.8) or nontransforming (P3HR1) virus strains. J. Virol. 62: 894 901.
88. Nalesnik, M. A.,, R. Jaffe,, T. E. Starzl,, A. J. Demetris,, K. Porter,, J. A. Burnham,, L. Makowka,, M. Ho,, and J. Locker. 1988. The pathology of posttransplant lymphoproliferative disorders occurring in the setting of cyclosporine A-prednisone immunosuppression. Am. J. Pathol. 133: 173 192.
89. Nerl, A.,, F. Barriga,, G. Inghirami,, D. M. Knowles,, J. Neequaye,, I. T. Magrath,, and R. Dalla Favera. 1991. Epstein-Barr virus infection precedes clonal expansion in Burkitt's and acquired immunodeficiency syndrome-associated lymphoma [see comments]. Blood 77: 1092 1095.
90. Niederman, J. C, R. W. McCollum, G. Henle, and W. Henle. 1968. Infectious mononucleosis. JAMA 203: 139 143.
91. Niedobitek, G.,, L. S. Young,, R. Lau,, L. Brooks,, D. Greenspan,, J. S. Greenspan,, and A. B. Rickinson. 1991. Epstein-Barr virus infection in oral hairy leukoplakia: virus replication in the absence of a detectable latent phase. J. Gen. Virol. 72: 3035 3046.
92. Old, L. J.,, A. E. Boyse,, H. F. Oettgen,, E. de Harven,, G. Geering,, E. Willamson,, and P. Clifford. 1966. Precipitating antibody in human serum to an antigen present in cultured Burkitt's lymphoma cells. Proc. Natl. Acad. Sci. USA 56: 1699 1704.
93. Pallesen, G.,, S. J. Hamilton Dutoit,, M. Rowe,, and L. S. Young. 1991. Expression of Epstein-Barr virus latent gene products in tumour cells of Hodgkin's disease [see comments]. Lancet 337: 320 322.
94.Pedersen, C, J. Gerstoft, J. D. Lundgren, P. Skinhoj, J. Bottzauw, C. Geisler, S. J. Hamilton Dutoit, S. Thorsen, I. Lisse, E. Ralfkiaer, et al. 1991. HIV-associated lymphoma: histopathology and association with Epstein-Barr virus genome related to clinical, immunological and prognostic features. Eur. J. Cancer 27: 14161423.
95. Pisa, P.,, M. J. Cannon,, E. K. Pisa,, N. R. Cooper,, and R. I. Fox. 1992. Epstein-Barr virus induced lymphoproliferative tumors in severe combined immunodeficient mice are oligoclonal. Blood 79: 173 179.
96. Pope, J. H.,, M. K. Home,, and W. Scott. 1968. Transformation of fetal human leucocytes in vitro by filtrates of a human leukemic cell line containing herpes-like virus. Int. J. Cancer 3: 857 866.
97. Porta, G.,, S. MacMillan,, R. Nagaraja,, S. Mumm,, I. Zucchi,, G. Pilla,, S. Maio,, T. Featherstone,, and D. Schlessinger. 1997. 4.5-Mb YAC STS contig at 50-kb resolution, spanning Xq25 deletions in two patients with lymphoproliferative syndrome. Genome Res. 7: 27 36.
98. Pracher, E.,, E. R. Panzer Grumayer,, A. Zoubek,, C. Peters,, and H. Gadner. 1994. Successful bone marrow transplantation in a boy with X-linked lymphoproliferative syndrome and acute severe infectious mononucleosis. Bone Marrow Transplant. 13: 655 658.
99. Purtilo, D. T. 1985. Epstein-Barr virus-induced diseases in the X-linked lymphoproliferative syndrome and related disorders. Biomed. Pharmacother. 39: 52 58.
100. Purtilo, D. T.,, and H. L. Grierson. 1991. Methods of detection of new families with X-linked lymphoproliferative disease. Cancer Genet. Cytogenet. 51: 143 153.
101. Purtilo, D. T.,, H. L. Grierson,, J. R. Davis,, and M. Okano. 1991. The X-linked lymphoproliferative disease: from autopsy toward cloning the gene 1975-1990. Pediatr. Pathol. 11: 685 710.
102. Raab Traub, N.,, and K. Flynn. 1986. The structure of the termini of the Epstein-Barr virus as a marker of clonal cellular proliferation. Cell 47: 883 889.
103. Randhawa, P. S.,, R. S. Markin,, T. E. Starzl,, and A. J. Demetris. 1990. Epstein-Barr virus-associated syndromes in immunosuppressed liver transplant recipients. Clinical profile and recognition on routine allograft biopsy. Am. J. Surg. Pathol. 14: 538 547.
104. Resnick, L.,, J. S. Herbst,, D. V. Ablashi,, S. Atherton,, B. Frank,, L. Rosen,, and S. N. Horwitz. 1988. Regression of oral hairy leukoplakia after orally administered acyclovir therapy. JAMA 259: 384 388.
105. Rickinson, A. B.,, M. Rowe,, I. J. Hart,, Q. Y. Yao,, L. E. Henderson,, H. Rabin,, and M. A. Epstein. 1984. T-cell-mediated regression of "spontaneous" and of Epstein-Barr virus-induced B-cell transformation in vitro: studies with cyclosporin A. Cell Immunol. 87: 646 658.
106. Rooney, C. M.,, C. A. Smith,, C. Y. Ng,, S. Loftin,, C. Li,, R. A. Krance,, M. K. Brenner,, and H. E. Heslop. 1995. Use of gene-modified virus-specific T lymphocytes to control Epstein-Barr-virus-related lymphoproliferation. Lancet 345: 9 13.
107. Rowe, M.,, D. T. Rowe,, C. D. Gregory,, L. S. Young,, P. J. Farrell,, H. Rupani,, and A. B. Rickinson. 1987. Differences in B cell growth phenotype reflect novel patterns of Epstein-Barr virus latent gene expression in Burkitt's lymphoma cells. EMBO J. 6: 2743 2751.
108. Rowe, M.,, L. S. Young,, J. Crocker,, H. Stokes,, S. Henderson,, and A. B. Rickinson. 1991. Epstein-Barr virus (EBV)-associated lymphoproliferative disease in the SCID mouse model: implications for the pathogenesis of EBV-positive lymphomas in man. J. Exp. Med. 173: 147 158.
109. Sandler, A. S.,, and L. Kaplan. 1996. AIDS lymphoma. Curr. Opin. Oncol. 8: 377 385.
110. Sandvej, K.,, L. Krenacs,, S. J. Hamilton Dutoit,, J. L. Rindum,, J. J. Pindborg,, and G. Pallesen. 1992. Epstein-Barr virus latent and replicative gene expression in oral hairy leukoplakia. Histopathology 20: 387 395.
111. Shapiro, R. S.,, A. Chauvenet,, W. McGuire,, A. Pearson,, A. W. Craft,, P. McGlave,, and A. Filipovich. 1988. Treatment of B-cell lymphoproliferative disorders with interferon alfa and intravenous gamma globulin [letter]. N. Engl. J. Med. 318: 1334.
112. Shiramizu, B.,, B. Herndier,, T. Meeker,, L. Kaplan,, and M. McGrath. 1992. Molecular and immunophenotypic characterization of AIDS-associated, Epstein-Barr virus-negative, polyclonal lymphoma [see comments]. J. Clin. Oncol. 10: 383 389.
113. Shope, T.,, D. Dechairo,, and G. Miller. 1973. Malignant lymphomas in cotton top marmosets following inoculation of Epstein-Barr virus. Proc. Natl. Acad. Sci. USA 70: 2487 2491.
114. Sixbey, J. W.,, and J. S. Pagano. 1985. Epstein-Barr virus transformation of human B lymphocytes despite inhibition of viral polymerase. J. Virol. 53: 299 301.
115. Sixbey, J. W.,, P. Shirley,, M. Sloas,, N. Raab Traub,, and V. Israele. 1991. A transformation-incompetent, nuclear antigen 2-deleted Epstein-Barr virus associated with replicative infection. J. Infect. Dis. 163: 1008 1015.
116. Smith, C. A.,, C. Y. Ng,, H. E. Heslop,, M. S. Holladay,, S. Richardson,, E. V. Turner,, S. K. Loftin,, C. Li,, M. K. Brenner,, and C. M. Rooney. 1995. Production of genetically modified Epstein-Barr virus-specific cytotoxic T cells for adoptive transfer to patients at high risk of EBV-associated lymphoproliferative disease. J. Hematother. 4: 73 79.
117. Smith, C. A.,, C. Y. Ng,, S. K. Loftin,, C. Li,, H. E. Heslop,, M. K. Brenner,, and C. M. Rooney. 1996. Adoptive immunotherapy for Epstein-Barr virus-related lymphoma. Leuk. Lymphoma 23: 213 220.
118. Straus, D. J. 1997. Human immunodeficiency virus-associated lymphomas. Med. Clin. North. Am. 81: 495 510.
119. Taub, R.,, I. Kirsch,, C. Morton,, G. Lenoir,, D. Swan,, S. Tronick,, S. Aaronson,, and P. Leder. 1982. Translocation of the c-myc gene into the immunoglobulin heavy chain locus in human Burkitt's lymphoma and murine plasmacytoma cells. Proc. Natl. Acad. Sci. USA 79: 7837 7841.
120. Thomas, J. A.,, D. H. Felix,, D. Wray,, J. C. Southam,, H. A. Cubie,, and D. H. Crawford. 1991. Epstein-Barr virus gene expression and epithelial cell differentiation in oral hairy leukoplakia. Am. J. Pathol. 139: 1369 1380.
121. Thomas, J. A.,, N. A. Hotchin,, M. J. Allday,, P. Amlot,, M. Rose,, M. Yacoub,, and D. H. Crawford. 1990. Immunohistology of Epstein-Barr virus-associated antigens in B cell disorders from immunocompromised individuals. Transplantation 49: 944 953.
122. Tomkinson, B. E.,, R. Maziarz,, and J. L. Sullivan. 1989. Characterization of the T cell-mediated cellular cytotoxicity during acute infectious mononucleosis. J. Immunol. 143: 660 670.
123. Tomkinson, B. E.,, D. K. Wagner,, D. L. Nelson,, and J. L. Sullivan. 1987. Activated lymphocytes during acute Epstein-Barr virus infection. J. Immunol. 139: 3802 3807.
124. Tosato, G. 1987. The Epstein-Barr virus and the immune system. Adv. Cancer Res. 49: 75 125.
125. Tosato, G.,, and R. M. Blaese. 1985. Epstein-Barr virus infection and immunoregulation in man. Adv. Immunol. 37: 99 149.
126. Vowels, M. R.,, R. L. Tang,, V. Berdoukas,, D. Ford,, D. Thierry,, D. Purtilo,, and E. Gluckman. 1993. Brief report: correction of X-linked lymphoproliferative disease by transplantation of cord-blood stem cells [see comments], N. Engl. J. Med. 329: 1623 1625.
127. Walling, D. M.,, S. N. Edmiston,, J. W. Sixbey,, M. Abdel Hamid,, L. Resnick,, and N. Raab Traub. 1992. Coinfection with multiple strains of the Epstein-Barr virus in human immunodeficiency virus-associated hairy leukoplakia. Proc. Natl. Acad. Sci. USA 89: 6560 6564.
128. Wang, D.,, D. Liebowitz,, and E. Kieff. 1985. An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells. Cell 43: 831 840.
129. Wang, D.,, D. Liebowitz,, and E. Kieff. 1988. The truncated form of the Epstein-Barr virus latent-infection membrane protein expressed in virus replication does not transform rodent fibroblasts. J. Virol. 62: 2337 2346.
130. Wang, D.,, D. Liebowitz,, F. Wang,, C. Gregory,, A. Rickinson,, R. Larson,, T. Springer,, and E. Kieff. 1988. Epstein-Barr virus latent infection membrane protein alters the human B-lymphocyte phenotype: deletion of the amino terminus abolishes activity. J. Virol. 62: 4173 4184.
131. Wang, F.,, C. Gregory,, C. Sample,, M. Rowe,, D. Liebowitz,, R. Murray,, A. Rickinson,, and E. Kieff. 1990. Epstein-Barr virus latent membrane protein (LMP1) and nuclear proteins 2 and 3C are affectors of phenotypic changes in B lymphocytes: EBNA-2 and LMP1 cooperatively induce CD23. J. Virol. 64: 2309 2318.
132. Wang, Q.,, Y. Ishikawa Brush,, A. P. Monaco,, D. L. Nelson,, C. T. Caskey,, S. P. Pauly,, G. M. Lenoir,, and B. S. Sylla. 1993. Physical mapping of Xq24-25 around loci closely linked to the X-linked lymphoproliferative syndrome locus: an overlapping YAC map and linkage between DXS12, DXS42, and DXS37. Eur. J. Hum. Genet. 1: 64 71.
133. Williams, L. L.,, C. M. Rooney,, M. E. Conley,, M. K. Brenner,, R. A. Krance,, and H. E. Heslop. 1993. Correction of Duncan's syndrome by allogeneic bone marrow transplantation [see comments]. Lancet 342: 587 588.
134. Young, L.,, C. Alfieri,, K. Hennessy,, H. Evans,, O. H. C,, K. C. Anderson,, J. Ritz,, R. S. Shapiro,, A. Rickinson,, E. Kieff,, and J. Cohen. 1989. Expression of Epstein-Barr virus transformation-associated genes in tissues of patients with EBV lymphoproliferative disease. N. Engl. J. Med. 321: 1080 1085.
135. Young, L. S.,, C. W. Dawson,, D. Clark,, H. Rupani,, P. Busson,, T. Tursz,, A. Johnson,, and A. B. Rickinson. 1988. Epstein-Barr virus gene expression in nasopharyngeal carcinoma. J. Gen. Virol. 69: 1051 1065.
136. Young, L. S.,, S. Finerty,, L. Brooks,, F. Scullion,, A. B. Rickinson,, and A. J. Morgan. 1989. Epstein-Barr virus gene expression in malignant lymphomas induced by experimental virus infection of cottontop tamarins. J. Virol. 63: 1967 1974.
137. Yu, M. C, J. H. Ho, S. H. Lai, and B. E. Henderson. 1986. Cantonese-style salted fish as a cause of nasopharyngeal carcinoma: report of a case-control study in Hong Kong. Cancer Res. 46: 956 961.
138.Zeng, Y, L. G. Zhang, Y. C. Wu, Y. S. Huang, N. Q. Huang, J. Y. Li, Y. B. Wang, M. K. Jiang, Z. Fang, and N. N. Meng. 1985. Prospective studies on nasopharyngeal carcinoma in Epstein-Barr virus IgA/VCA antibody-positive persons in Wuzhou City, China. Int. J. Cancer 36: 545547.
139. Ziegler, J. L.,, J. A. Beckstead,, P. A. Volberding,, D. I. Abrams,, A. M. Levine,, R. J. Lukes,, P. S. Gill,, R. L. Burkes,, P. R. Meyer,, C. E. Metroka,, J. Mouradian,, A. Moore,, S. A. Riggs,, J. J. Butler,, F. C. Cabanillas,, E. Hersh,, G. R. Newell,, L. J. Laubenstein,, D. Knowles,, C. Odajnyk,, B. Raphael,, B. Koziner,, C. Urmacher,, and B. D. Clarkson. 1984. Non-Hodgkin's lymphoma in 90 homosexual men. Relation to generalized lymphadenopathy and the acquired immunodeficiency syndrome. N. Engl. J. Med. 311: 565 570.
140. zur Hausen, H.,, H. Schulte-Holthausen,, G. Klein,, W. Henle,, G. Henle,, P. Clifford,, and L. Santesson. 1970. EB-virus DNA in biopsies of Burkitt tumors and anaplastic carcinomas of the nasopharynx. Nature 228: 1056 1057.


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Table 1

Viral and cellular features of well-characterized EBV-associated malignancies

Citation: Liebowitz D. 1998. Pathogenesis of Epstein-Barr Virus, p 175-199. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch5

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