Beyond the Provirus: from Howard Temin's Insights on Rous Sarcoma Virus to the Study of Epstein-Barr Virus, the Prototypic HumanTumor Virus

Bill Sugden

doi:10.1128/9781555818302.ch12

Chapter 12 : Beyond the Provirus: from Howard Temin's Insights on Rous Sarcoma Virus to the Study of Epstein-Barr Virus, the Prototypic HumanTumor Virus

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Affiliations: 1: McArdle Laboratory for Cancer Research, University of Wisconsin, 1400 University Avenue, Madison, Wisconsin 53706

Content Type: Monograph

Publication Year: 1995

Category: Viruses and Viral Pathogenesis; Microbial Genetics and Molecular Biology

Book DOI: 10.1128/9781555818302

Chapter DOI: 10.1128/9781555818302.ch12

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Abstract:

This chapter focuses on the development of one's understanding of carcinogenesis mediated by avian retroviruses, to which Howard Temin contributed so much. This understanding, coupled with the associated study of retroviruses in general, has been essential to dealing effectively with human disease. It also outlines current appreciation of human tumor viruses, using Epstein-Barr virus (EBV) as a model. Human tumor viruses are less efficient pathogens than most of the well-studied avian oncogenic retroviruses. Howard Temin refined a transformation assay for Rous sarcoma virus (RSV) such that it became a standard method for detecting and measuring the transforming abilities of different viruses in cell culture. Avian leukosis viruses (ALVs) provide one example of weakly transforming viruses. These viruses formerly often infected commercial flocks of chickens, in which they were propagated either vertically or horizontally. Four human tumor viruses-EBV (a herpesvirus), hepatitis B virus (HBV), human papilloma virus types 16 (HPV-16), -18, -31, and -33, and human T-cell leukemia virus type 1 (HTLV-1; a retrovirus)-have been studied sufficiently to be considered in this chapter. A fifth, hepatitis C virus, has been identified, but virologic studies of it are only now beginning. The outcome of infection with some human tumor viruses can be profoundly affected by the immune response of the host. The four human tumor viruses (EBV, HBV, HPV, and HTLV-1 ) vary in the cell types they infect, in the times between infection and development of cancers, and in the mechanisms by which they induce and/or maintain proliferation of infected cells.

Citation: Sugden B. 1995. Beyond the Provirus: from Howard Temin's Insights on Rous Sarcoma Virus to the Study of Epstein-Barr Virus, the Prototypic HumanTumor Virus, p 161-184. In Cooper G, Temin R, Sugden B (ed), The DNA Provirus. ASM Press, Washington, DC. doi: 10.1128/9781555818302.ch12

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Beyond the Provirus: from Howard Temin's Insights on Rous Sarcoma Virus to the Study of Epstein-Barr Virus, the Prototypic HumanTumor Virus

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Figure 1

Synopsis of steps proposed to occur between infection with these different model tumor viruses and development of their associated tumors. The order in which the steps occur is consistent with current understanding of the etiologies of these virus-associated tumors but is hypothetical. Ig, immunoglobulin.

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Figure 1

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Figure 2

Synopsis of the shared and different steps proposed to occur between infection with EBV and the development of a benign lymphoproliferative disease (infectious mononucleosis) or a malignant one (Burkitt's lymphoma). Ig, immunoglobulin.

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Figure 2

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Figure 3

Map of the EBV genome, depicting transcripts expressed during the latent phase of the viral life cycle (adapted from reference 51 ). The circle represents the circular DNA of EBV joined at the terminal repeats (TR), as occurs in latently infected cells. The letters and slash marks in the circle denote fragments of EBV DNA generated by digestion with BamHI endonuclease. oriP and oriLyt are the two origins of DNA replication of EBV; oriP is used during the latent phase of the viral life cycle, and oriLyt is used during the lytic phase. Arrows represent start sites for transcription used during the EBV latent phase and considered in this chapter. Open boxes following the arrows are coding sequences for translation of EBV latent genes (EBNA-LP is made up of the repeats within BamW, while EBNA-2 is made up of the single exon within BamY and BamH), and the dashed lines between them represent introns and untranslated exons.

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References

/content/book/10.1128/9781555818302.chap12

1. Abbot, S. D.,, M. Rowe,, K. Cadwallader,, A. Ricksten,, J. Gurdon,, F. Wang,, L. Rymo,, and A. B. Rickinson. 1990. Epstein-Barr virus nuclear antigen 2 induces expression of the virus-encoded latent membrane protein. J. Virol. 64: 2126– 2134.

2. Adams, A. 1987. Replication of latent Epstein-Barr virus genomes in Raji cells. J. Virol. 61: 1743– 1746.

3. Alfieri, C.,, M. Birkenbach,, and E. Kieff. 1991. Early events in Epstein-Barr virus infection of human B lymphocytes. Virology 181: 595– 608.

4. Allday, M. J.,, and P. J. Farrell. 1994. Epstein-Barr virus nuclear antigen EBNA 3C/6 expression maintains the level of latent membrane protein 1 in G 1-arrested cells. J. Virol. 68: 3491– 3498.

5. Anderson, P. N.,, and M. Potter. 1969. Induction of plasma cell tumors in BALB/c mice with 2,6,10,14-tetramethylpentadecone (pristane). Nature (London) 222: 994– 995.

6. Baba, T. W.,, and E. H. Humphries. 1985. Formation of a transformed follicle is necessary but not sufficient for development of an avian leukosis virus-induced lymphoma. Proc. Natl. Acad. Sci. USA 82: 213– 216.

7. Baichwal, V. R.,, and B. Sugden. 1987. Posttranslational processing of an Epstein-Barr virus-encoded membrane protein expressed in cells transformed by Epstein-Barr virus. J. Virol. 61: 866– 875.

8. Baichwal, V. R.,, and B. Sugden. 1989. Transformation of BALB 3T3 cells by the BNLF-1 gene of Epstein-Barr virus. Oncogene 2: 461– 467.

9. Banchereau, J.,, P. de Paoli,, A. Valle,, E. Garcia,, and F. Rousset. 1991. Long-term human B cell lines dependent on interleukin-4 and antibody to CD40. Science 251: 70– 72.

10. Beasley, R. P. Hepatitis B virus. Cancer 61: 1942– 1956.

11. Blacklow, N. R.,, B. K. Watson,, G. Miller,, and B. M. Jacobson. 1971. Mononucleosis with heterophile antibodies and EB virus infection. Acquisition by an elderly patient in hospital. Am. J. Med. 51: 549– 552.

12. Bodescot, M.,, and M. Perricaudet. 1986. Epstein-Barr virus mRNAs produced by alternative splicing. Nucleic Acids Res. 17: 7130– 7134.

13. Burkitt, D. 1962. A children’s cancer dependent upon climatic factors. Nature (London) 194: 232– 234.

14. Burrows, S. R.,, J. Gardner,, R. Khanna,, T. Steward,, D. J. Moss,, S. Rodda,, and A. Suhrbier. 1994. Five new cytotoxic T cell epitopes identified within Epstein-Barr virus nuclear antigen 3. J. Gen. Virol. 75: 2489– 2493.

15. Cartwright, C. A.,, W. Eckhart,, S. Simon,, and P. L. Kaplan. 1987. Cell transformation by pp60 c-src mutated in the carboxy-terminal regulatory domain. Cell 49: 83– 91.

16. Chellappan, S.,, V. B. Kraus,, B. Kroger,, K. Munger,, P. M. Howley,, W. C. Phelps,, and J. R. Nevins. 1992. Adenovirus E1A, simian virus 40 tumor antigen, and human papillomavirus E7 protein share the capacity to disrupt the interaction between transcription factor E2F and the retinoblastoma gene product. Proc. Natl. Acad. Sci. USA 89: 4549– 4553.

17. Cooper, J. A.,, K. L. Gould,, C. A. Cartwright,, and J. Hunter. 1986. Tyr 527 is phosphorylated in pp60 c-src: implications for regulation. Science 231: 1431– 1434.

18. Cordier, M.,, A. Calender,, M. Billand,, V. Zimber,, G. Rousselet,, O. Pavish,, J. Banchereau,, T. Tursz,, G. Bornkamm,, and G. M. Lenoir. 1990. Stable transfection of Epstein-Barr virus (EBV) nuclear antigen 2 in lymphoma cells containing the EBV P3HR1 genome induces expression of B-cell activation molecules CD21 and CD23. J. Virol. 64: 1002– 1013.

19. Craig, F. E.,, M. L. Gully,, and P. M. Banks. 1993. Post-transplantation lymphoproliferative disorders. Am. J. Clin. Pathol. 99: 265– 276.

20. Dawson, C. W.,, A. B. Rickinson,, and L. S. Young. 1990. Epstein-Barr virus latent membrane protein inhibits human epithelial cell differentiation. Nature (London) 344: 777– 780.

21. de-Thé, G.,, A. Geser,, N. E. Day,, P. M. Tukei,, E. H. Williams,, D. P. Beri,, P. G. Smith,, A. G. Dean,, G. W. Bornkamm,, P. Feorino,, and W. Henle. 1978. Epidemiological evidence for causal relationship between Epstein-Barr virus and Burkitt’s lymphoma from Ugandan prospective study. Nature (London) 274: 756– 761.

22. Dyson, N.,, P. M. Howley,, K. Munger,, and E. Harlow. 1989. The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 243: 934– 937.

23. Edwards, R. H.,, and N. Raab-Traub. 1994. Alterations of the p53 gene in Epstein-Barr virus-associated immunodeficiency-related lymphomas. J. Virol. 68: 1309– 1315.

24. Evans, A. S., 1982. The transmission of EB viral infections, p. 211– 225. In J. J. Hooks, and G. W. Jordan (ed.), Viral Infections in Oral Medicine. Elsevier/North Holland, New York.

25. Facer, C. A.,, and J. H. L. Playfair. 1989. Malaria, Epstein-Barr virus, and the genesis of lymphomas. Adv. Cancer Res. 55: 33– 72.

26. Fåhraeus, R.,, A. Jansson,, A. Ricksten,, A. Sjoblom,, and L. Rymo. 1990. Epstein-Barr virus-encoded nuclear antigen 2 activates the viral latent membrane protein promoter by modulating the activity of a negative regulatory element. Proc. Natl. Acad. Sci. USA 87: 7390– 7394.

27. Fåhraeus, R.,, L. Rymo,, J. S. Rhim,, and G. Klein. 1990. Morphological transformation of human keratinocytes expressing the LMP gene of Epstein-Barr virus. Nature (London) 345: 447– 449.

28. Farrell, P. J.,, G. J. Allan,, F. Shanahan,, K. H. Vousden,, and T. Crook. 1991. p53 is frequently mutated in Burkitt’s lymphoma cell lines. EMBO J. 10: 2879– 2887.

29. Fialkow, P. J.,, G. Klein,, S. M. Gartler,, and P. Clifford. 1970. Clonal origin for individual Burkitt tumors. Lancet i: 384– 386.

30. Fingeroth, J. D.,, J. J. Weis,, T. F. Tedder,, J. L. Strominger,, P. A. Biro,, and D. T. Fearon. 1984. Epstein-Barr virus receptor of human B lymphocytes is the C3d receptor CR2. Proc. Natl. Acad. Sci. USA 81: 4510– 4514.

31. Gahn, T. A.,, and C. L. Schildkraut. 1989. The Epstein-Barr virus origin of plasmid replication, oriP, contains both the initiation and termination sites of DNA replication. Cell 58: 527– 535.

32. Gahn, T. A.,, and B. Sugden. 1995. An EBNA-1 dependent enhancer acts from a distance of 10 kilobase pairs to increase expression of the Epstein-Barr virus LMP gene. J. Virol. 69: 2633– 2636.

33. Gaidano, G.,, P. Ballerini,, J. Z. Gong,, G. Inghirami,, A. Neri,, E. W. Newcomb,, I. T. Magrath,, D. M. Knowles,, and R. Dalla-Favera. 1991. p53 Mutations in human lymphoid malignancies: association with Burkitt lymphoma and chronic lymphocytic leukemia. Proc. Natl. Acad. Sci. USA 88: 5413– 5417.

34. Gelman, I. H.,, and H. Hanafusa. 1989. Suppression of Rous sarcoma virus-induced tumor formation by preinfection with viruses encoding src protein with novel N termini. J. Virol. 63: 2461– 2468.

35. Gelman, I. H.,, and H. Hanafusa. 1993. src-specific immune regression of Rous sarcoma virus-induced tumors. Cancer Res. 53: 915– 920.

36. Geser, A. D.,, G. deThe,, G. Lenoir,, N. E. Day,, and E. H. Williams. 1982. Final case reporting from the Uganda prospective study of the relationship between EBV and Burkitt’s lymphoma. Int. J. Cancer 29: 397– 400.

37. Giuliano, V. J.,, H. E. Jasin,, and M. Ziff. 1974. The nature of the atypical lymphocyte in infectious mononucleosis. Clin. Immunol. Immunopathol. 3: 90– 98.

38. Gregory, C. D.,, R. J. Murray,, C. F. Edwards,, and A. B. Rickinson. 1988. Down-regulation 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.

39. Hammerschmidt, W.,, and B. Sugden. 1989. Genetic analysis of immortalizing functions of Epstein-Barr virus in human B-lymphocytes. Nature (London) 340: 393– 397.

40. Hammerskjöld, M.,, and M. Simurda. 1992. Epstein-Barr latent membrane protein transactivates the human immunodeficiency virus type 1 long terminal repeat through induction of NF-κ B activity. J. Virol. 66: 6496– 6501.

41. Hanto, D. W.,, G. Frizzera,, D. T. Purtilo,, K. Sakamoto,, J. L. Sullivan,, A. K. Saemundsen,, G. Klein,, R. L. Simmons,, and J. S. Najarian. 1981. Clinical spectrum of lymphoproliferative disorders in renal transplant recipients and evidence for the role of the Epstein-Barr virus. Cancer Res. 41: 4253– 4261.

42. Hawley-Nelson, P.,, K. H. Vousden,, N. L. Hubbert,, D. R. Lowy,, and J. T. Schiller. 1989. HPV16 E6 and E7 proteins cooperate to immortalize human foreskin keratinocytes. EMBO J. 8: 3905– 3910.

43. Hayward, W. S.,, B. G. Neel,, and S. M. Astrin. 1981. Activation of a cellular onc gene by promoter insertion in ALV-induced lymphoid leukosis. Nature (London) 290: 475– 480.

44. Henderson, E.,, G. Miller,, J. Robinson,, and L. Heston. 1977. Efficiency of transformation of lymphocytes by Epstein-Barr virus. Virology 76: 152– 163.

45. 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.

46. Imamoto, A.,, and P. Soriano. 1993. Disruption of the csk gene, encoding a negative regulator of src family tyrosine kinases, leads to neural tube defects and embryonic lethality in mice. Cell 73: 1117– 1124.

47. Inoue, J.,, M. Seiki,, T. Taniguchi,, S. Tsuru,, and M. Yoshida. 1986. Induction of interleukin 2 receptor gene expression by p40 encoded by human T-cell leukemia virus type I. EMBO J. 5: 2883– 2888.

48. Jove, R.,, and H. Hanafusa. 1987. Cell transformation by the viral src oncogene. Annu. Rev. Cell Biol. 3: 31– 56.

49. 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.

50. Keath, E. J.,, A. Keleker,, and M. Cole. 1984. Transcriptional activation of the translocated c- myc oncogene in mouse plasmacytomas: similar RNA levels in tumor and proliferating normal cells. Cell 37: 521– 528.

51. Kempkes, B.,, D. Pich,, R. Zeidler,, B. Sugden,, and W. Hammerschmidt. 1995. Immortalization of human B lymphocytes by a plasmid containing 71 kilobase pairs of Epstein-Barr virus DNA. J. Virol. 69: 231– 238.

52. Kempkes, B.,, D. Spitkovsky,, P. Jansen-Dunn,, J. W. Ellwart,, E. Kremmer,, H.-J. Delecluse,, C. Rottenberger,, G. W. Bornkamm,, and W. Hammerschmidt. 1995. B-cell proliferation and induction of early G 1-regulating proteins by Epstein-Barr virus mutants conditional for EBNA2. EMBO J. 14: 88– 96.

53. 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.

54. Kinoshita, T.,, M. Shimoyama,, K. Tobinai,, M. Ito,, S. Ito,, S. Ikeda,, K. Tajima,, K. Shimotohno,, and T. Sugimura. 1989. Detection of mRNA for the tax 1/rex 1 gene of human T cell leukemia virus type 1 in fresh peripheral blood mononuclear cells of adult T-cell leukemia patients and viral carriers by using the polymerase chain reaction. Proc. Natl. Acad. Sci. USA 86: 5620– 5624.

55. Kintner, C.,, and B. Sugden. 1981. Identification of antigenic determinants unique to the surfaces of cells transformed by Epstein-Barr virus. Nature (London) 294: 458– 460.

56. Kirchmaier, A.,, and B. Sugden. 1995. Plasmid maintenance of derivatives of oriP of Epstein-Barr virus. J. Virol. 69: 1280– 1283.

57. Klein, G. 1994. Epstein-Barr virus strategy in normal and neoplastic B cells. Cell 77: 791– 793.

58. Kmiecik, T. E.,, and D. Shalloway. 1987. Activation and suppression of pp60 c-src transforming ability by mutation of its primary sites of tyrosine phosphorylation. Cell 49: 65– 73.

59. Laherty, C. D.,, H. M. Hu,, A. W. Opipari,, F. Wang,, and V. M. Dixit. 1992. The Epstein-Barr virus LMP1 gene product induces A20 zinc finger protein expression by activating nuclear factor κ B. J. Biol. Chem. 34: 24157– 24160.

60. Lam, K. M. C.,, N. Syed,, H. Whittle,, and D. H. Crawford. 1991. Circulating Epstein-Barr virus-carrying B cells in acute malaria. Lancet 337: 876– 878.

61. Lambert, P. F.,, H. Pan,, H. C. Pitot,, A. Liem,, M. Jackson,, and A. E. Griep. 1993. Epidermal cancer associated with expression of human papillomavirus type 16 E6 and E7 oncogenes in the skin of transgenic mice. Proc. Natl. Acad. Sci. USA 90: 5583– 5587.

62. Laux, G.,, M. Perricaudet,, and P. J. Farrell. 1988. A spliced Epstein-Barr virus gene expressed in latently transformed lymphocytes is created by circularization of the linear viral genome. EMBO J. 7: 769– 774.

63. Leibowitz, D.,, R. Kopan,, E. Fuchs,, J. Sample,, and E. Kieff. 1987. An Epstein-Barr virus transforming protein associates with vimentin in lymphocytes. Mol. Cell. Biol. 7: 2299– 2308.

64. Leibowitz, D.,, D. Wang,, and E. Kieff. 1986. Orientation and patching of the latent infection membrane protein encoded by Epstein-Barr virus. J. Virol. 58: 233– 237.

65. Lewin, N.,, P. Åman,, M. G. Masucci,, E. Klein,, G. Klein,, B. Öberg,, H. Strander,, W. Henle,, and G. Henle. 1987. Characterization of EBV-carrying B-cell populations in healthy seropositive individuals with regard to density, release of transforming virus and spontaneous outgrowth. Int. J. Cancer 39: 472– 476.

66. Ling, P. D.,, D. R. Rawlins,, and S. D. Hayward. 1993. The Epstein-Barr virus immortalizing protein EBNA-2 is targeted to DNA by a cellular enhancer-binding protein. Proc. Natl. Acad. Sci. USA 90: 9237– 9241.

67. Lowe, S. W.,, S. Bodis,, A. McClatchey,, L. Remington,, H. E. Ruley,, D. E. Fisher,, D. E. Housman,, and T. Jacks. 1994. p53 status and the efficacy of cancer therapy in vivo. Science 266: 807– 810.

68. Mann, K. P.,, D. Staunton,, and D. A. Thorley-Lawson. 1985. Epstein-Barr virus-encoded protein in plasma membranes of transformed cells. J. Virol. 55: 710– 720.

69. Mannick, J. B.,, J. Cohen,, M. Birkenbach,, A. Marchini,, and E. Kieff. 1991. The Epstein-Barr virus nuclear protein encoded by the leader of the EBNA RNAs (EBNA-LP) is important in B-lymphocyte transformation. J. Virol. 65: 6829– 6837.

70. Mark, W.,, and B. Sugden. 1982. Transformation of lymphocytes by Epstein-Barr virus requires only one-fourth of the viral genome. Virology 122: 431– 443.

71. Martin, J. M.,, and B. Sugden. 1991. The LMP oncoprotein resembles activated receptors in its properties of turnover. Cell Growth Differ. 2: 653– 660.

72. Martin, J. M.,, and B. Sugden. 1991. Transformation by the oncogenic latent membrane protein correlates with its rapid turnover, membrane localization, and cytoskeletal association. J. Virol. 65: 3246– 3258.

73. Martin, J. M.,, D. Veis,, S. J. Korsmeyer,, and B. Sugden. 1993. Latent membrane protein of Epstein-Barr virus induces cellular phenotypes independently of expression of Bcl-2. J. Virol. 67: 5269– 5278.

74. Miller, C. L.,, J. H. Lee,, E. Kieff,, and R. Longnecker. 1994. An integral membrane protein (LMP2) blocks reactivation of Epstein-Barr virus from latency following surface immunoglobulin cross-linking. Proc. Natl. Acad. Sci. USA 91: 772– 776.

75. Miller, G.,, D. Coope,, J. Niederman,, and J. Pagano. 1976. Biological properties and viral surface antigens of Burkitt lymphoma- and mononucleosis-derived strains of Epstein-Barr virus released from transformed marmoset cells. J. Virol. 18: 1071– 1080.

76. Mitchell, T.,, and B. Sugden. 1995. Stimulation of NF-κ B-mediated transcription by mutant derivatives of the latent membrane protein of Epstein-Barr virus. J. Virol. 69: 2968– 2976.

77. Miyoshi, I.,, I. Kubonishi,, S. Yoshimoto,, T. Akagi,, Y. Ohtsuki,, Y. Shiroishi,, K. Nagata,, and Y. Hinuma. 1981. Type C virus particles in a cord T cell line derived by co-cultivating normal human cord leukocytes with human leukemic T cells. Nature (London) 294: 770– 772.

78. Moriyama, T.,, S. Guilhot,, K. Klopchin,, B. Moss,, C. A. Pinkert,, R. D. Palmiter,, R. L. Brinster,, O. Kanagawa,, and F. V. Chisar. 1990. Immunobiology and pathogenesis of hepatocellular injury in hepatitis B virus transgenic mice. Science 248: 361– 364.

79. Morrow, R. H.,, A. Kisuule,, M. C. Pike,, and P. G. Smith. 1976. Burkitt’s lymphoma in the Mengo districts of Uganda: epidemiologic features and their relationship to malaria. J. Natl. Cancer Inst. 56: 479– 486.

80. Mosier, D. E.,, S. M. Baird,, M. B. Kirven,, R. J. Gulizia,, D. B. Wilson,, R. Kubayashi,, G. Picchio,, J. L. Garnier,, J. L. Sullivan,, and T. J. Kipps. 1990. EBV-associated B-cell lymphomas following transfer of human peripheral blood lymphocytes to mice with severe combined immunodeficiency. Curr. Top. Microbiol. Immunol. 166: 317– 323.

81. Murray, R. J.,, M. G. Kurilla,, H. M. Griffin,, J. M. Brooks,, M. Mackett,, J. R. Arrand,, M. Rowe,, S. R. Burrows,, D. J. Moss,, E. Kieff,, and A. B. Rickinson. 1990. Human cytotoxic T-cell responses against Epstein-Barr virus nuclear antigens demonstrated by using recombinant vaccinia viruses. Proc. Natl. Acad. Sci. USA 87: 2906– 2910.

82. Nada, S.,, T. Yagi,, H. Takeda,, T. Tokunaga,, H. Nakagawa,, Y. Ikawa,, M. Okada,, and S. Aizawa. 1993. Constitutive activation of src family kinases in mouse embryos that lack csk. Cell 73: 1125– 1135.

83. Nemerow, G. R.,, C. Mold,, V. K. Schwend,, V. Tollefson,, and N. R. Cooper. 1987. Identification of gp350 as the viral glycoprotein mediating attachment of Epstein-Barr virus (EBV) to the EBV/C3d receptor of B cells: sequence homology of gp350 and C3 complement fragment C3d. J. Virol. 61: 1416– 1420.

84. Nkrumah, F.,, W. Henle,, G. Henle,, R. Herberman,, V. Perkins,, and R. Depue. 1976. Burkitt’s lymphoma: its clinical course in relation to immunologic reactivities to Epstein-Barr virus and tumor related antigens. J. Natl. Cancer Inst. 57: 1051– 1056.

85. Ohno, S.,, M. Babonits,, F. Wiener,, J. Spira,, G. Klein,, and M. Potter. 1979. Non-random chromosome changes involving the 1g-gene carrying chromosomes 12 and 6 in pristane-induced mouse plasmacytomas. Cell 18: 1001– 1007.

86. Okada, M.,, and H. Nakagawa. 1989. A protein tyrosine kinase involved in regulation of pp60 c-csr function. J. Biol. Chem. 264: 20886– 20893.

87. Payne, G. S.,, J. M. Bishop,, and H. E. Varmus. 1982. Multiple arrangements of viral DNA and an activated host oncogene in bursal lymphomas. Nature (London) 295: 209– 214.

88. Payne, L. N.,, and H. G. Purchase,. 1991. Leukosis/sarcoma group, p. 386– 439. In B. W. Calnek (ed.), Diseases of Poultry, 9th ed. Iowa State University Press, Ames.

89. Peng, M.,, and E. Lundgren. 1992. Transient expression of the Epstein-Barr virus LMP1 gene in human primary B cells induces cellular activation and DNA synthesis. Oncogene 7: 1775– 1782.

90. Piwnica-Worms, H.,, K. B. Saunders,, T. M. Roberts,, A. E. Smith,, and S. H. Cheng. 1987. Tyrosine phosphorylation regulates the biochemical and biological properties of pp60 c-src. Cell 49: 75– 82.

91. Qu, L.,, and D. T. Rowe. 1992. Epstein-Barr virus latent gene expression in uncultured peripheral blood lymphocytes. J. Virol. 66: 3715– 3724.

92. Rawlins, D. R.,, G. Milman,, S. D. Hayward,, and G. S. Hayward. 1985. Sequence-specific DNA binding of the Epstein-Barr virus nuclear antigen (EBNA-1) to clustered sites in the plasmid maintenance region. Cell 42: 859– 868.

93. Reisman, D.,, and B. Sugden. 1986. trans activation of an Epstein-Barr viral transcriptional enhancer by the Epstein-Barr viral nuclear antigen 1. Mol. Cell. Biol. 6: 3838– 3846.

94. Reisman, D.,, J. Yates,, and B. Sugden. 1985. A putative origin of replication of plasmids derived from Epstein-Barr virus is composed of two cis-acting components. Mol. Cell. Biol. 5: 1822– 1832.

95. Resh, M. D. 1994. Myristylation and palmitylation of src family members: the fats of the matter. Cell 76: 411– 413.

96. Robinson, J.,, D. Smith,, and J. Niederman. 1980. Mitotic EBNA-positive lymphocytes in peripheral blood during infectious mononucleosis. Nature (London) 287: 334– 336.

97. Robinson, J. E.,, D. Smith,, and J. Niederman. 1981. Plasmacytic differentiation of circulating Epstein-Barr virus-infected B lymphocytes during acute infectious mononucleosis. J. Exp. Med. 153: 235– 244.

98. Rogers, R. P.,, M. Woisetschlaeger,, and S. H. Speck. 1990. Alternative splicing dictates translational start in Epstein-Barr virus transcripts. EMBO J. 9: 2273– 2277.

99. Rooney, C.,, J. G. Howe,, S. H. Speck,, and G. Miller. 1989. Influences of Burkitt’s lymphoma and primary B-cells on latent gene expression by the nonimmortalizing P3J-HR-1 strain of Epstein-Barr virus. J. Virol. 63: 1531– 1539.

100. Rowe, D. T.,, M. Rowe,, G. I. Evan,, L. E. Wallace,, P. J. Farrell,, and A. B. Rickinson. 1986. Restricted expression of EBV latent genes and T-lymphocyte-detected membrane antigen in Burkitt’s lymphoma cells. EMBO J. 5: 2599– 2607.

101. 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.

102. Saewha, J.,, and P. Lambert. 1995. Integration of HPV-16 DNA into the human genome leads to increased stability of E6/E7 mRNAs: implications for cervical carcinogenesis. Proc. Nail. Acad. Sci. USA 92: 1654– 1658.

103. Sample, J.,, D. Liebowitz,, and E. Kieff. 1989. Two related Epstein-Barr virus membrane proteins are encoded by separate genes. J. Virol. 63: 933– 937.

104. Scheffner, M.,, J. M. Huibregtse,, R. D. Vierstra,, and P. M. Howley. 1993. The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 75: 495– 505.

105. Schubach, W. H.,, R. Hackman,, P. E. Neiman,, G. Miller,, and E. D. Thomas. 1982. A monoclonal immunoblastic sarcoma in donor cells bearing Epstein-Barr virus genomes following allogenic marrow grafting for acute lymphoblastic leukemia. Blood 60: 180– 187.

106. Schwartz, E.,, U. K. Freese,, L. Gissman,, W. Mayer,, B. Roggenbuck,, A. Stremlau,, and H. zur Hausen. 1985. Structure and transcription of human papilloma virus sequences in cervical carcinoma cells. Nature (London) 314: 111– 114.

107. Speck, S. H.,, and J. L. Strominger. 1989. Transcription of Epstein-Barr virus in latently infected, growth-transformed lymphocytes. Adv. Viral Oncol. 8: 133– 150.

108. Spencer, C. A.,, and M. Groudine. 1991. Control of c- myc regulation in normal and neoplastic cells. Adv. Cancer Res. 56: 1– 48.

109. Stanton, L. W.,, R. Watt,, and K. B. Marcu. 1983. Translocation, breakage, and truncated transcripts of c- myc oncogene in murine plasmacytomas. Nature (London) 303: 401– 406.

110. Stehelin, D.,, H. E. Varmus,, J. M. Bishop,, and P. K. Vogt. 1976. DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA. Nature (London) 260: 170– 173.

111.Sugden B. 1977. Comparison of Epstein-Barr viral DNAs in Burkitt lymphoma biopsy cells and in cells clonally transformed in vitro. Proc. Natl. Acad. Sci. USA 74: 4651– 4655.

112. Sugden, B. 1994. Latent infection of B-lymphocytes by Epstein-Barr virus. Semin. Virol. 5: 197– 205.

113. Sugden, B.,, and W. Mark. 1977. Clonal transformation of adult human leukocytes by Epstein-Barr virus. J. Virol. 23: 503– 508.

114. Sugden, B.,, and N. Warren. 1989. A promoter of Epstein-Barr virus that can function during latent infection can be transactivated by EBNA-1, a viral protein required for viral DNA replication during latent infection. J. Virol. 63: 2644– 2649.

115. Svedmyr, E.,, and M. Jondal. 1975. Cytotoxic effector cells specific for B cell lines transformed by Epstein-Barr virus are present in patients with infectious mononucleosis. Proc. Natl. Acad. Sci. USA 72: 1622– 1626.

116. Temin, H. M. 1974. On the origin of the genes for neoplasia: G. H. A. Clowes Memorial Lecture. Cancer Res. 34: 2835– 2841.

117. Temin, H. M.,, and H. Rubin. 1958. Characteristics of an assay for Rous sarcoma virus and Rous sarcoma cells in tissue culture. Virology 6: 669– 688.

118. Tierney, R. J.,, N. Steven,, L. S. Young,, and A. B. Rickinson. 1994. Analysis of viral gene transcription during primary infection and in the carrier state. J. Virol. 68: 7374– 7385.

119.Tomkinson B.,, E. Robertson,, and E. Kieff. 1993. Epstein-Barr virus nuclear proteins (EBNA) 3A and 3C are essential for B-lymphocyte growth transformation. J. Virol. 67: 2014– 2025.

120. Tsang, S.-F.,, F. Wang,, K. M. Izumi,, and E. Kieff. 1991. Delineation of the cis-acting element mediating EBNA-2 transactivation of latent infection membrane protein expression. J. Virol. 65: 6765– 6771.

121. Wang, D.,, D. Liebowitz,, and E. Kieff. 1985. An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells. Cell 43: 831– 840.

122. 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-Iymphocyte phenotype: deletion of the amino terminus abolishes activity. J. Virol. 62: 4173– 4184.

123. Wang, F.,, C. D. Gregory,, M. Rowe,, A. B. Rickinson,, D. Wang,, M. Birkenbach,, H. Kikutani,, T. Kishimoto,, and E. Kieff. 1987. Epstein-Barr virus nuclear antigen 2 specifically induces expression of the B-cell activation antigen CD23. Proc. Natl. Acad. Sci. USA 84: 3452– 3456.

124. 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 effectors of phenotypic changes in B lymphocytes: EBNA-2 and LMP1 cooperatively induce CD23. J. Virol. 64: 2309– 2318.

125. Wang, F.,, H. Kikutani,, S.-F. Tsang,, T. Kishimoto,, and E. Kieff. 1991. Epstein-Barr virus nuclear protein 2 transactivates a cis-acting CD23 DNA element. J. Virol. 65: 4101– 4106.

126. Wang, F.,, S. Tang,, M. G. Kurilla,, J. Cohen,, and E. Kieff. 1990. Epstein-Barr virus nuclear antigen 2 transactivates latent membrane protein LMP1. J. Virol. 64: 3407– 3416.

127. Werness, B. A.,, A. J. Levine,, and P. M. Howley. 1990. Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science 248: 76– 79.

128. Whittle, H. C.,, J. Brown,, K. Marsh,, B. M. Greenwood,, P. Seidelin,, H. Tighe,, and L. Wedderburn. 1984. T-cell control of Epstein-Barr virus-infected B cells is lost during P. falciparum malaria. Nature (London) 312: 449– 450.

129. Woisetschlaeger, M.,, C. N. Yandava,, L. A. Furmanski,, J. L. Strominger,, and S. H. Speck. 1990. Promoter switching in Epstein-Barr virus during the initial stages of infection of B lymphocytes. Proc. Natl. Acad. Sci. USA 87: 1725– 1729.

130. Yano, T.,, C. A. Sander,, H. M. Clark,, M. V. Dolezal,, E. S. Jaffe,, and M. Raffeld. 1993. Clustered mutation in the second exon of the MYC gene in sporadic Burkitt’s lymphoma. Oncogene 8: 2741– 2749.

131. Yao, Q. Y.,, A. B. Rickinson,, and M. A. Epstein. 1985. A re-examination of the Epstein-Barr virus carrier state in healthy sero-positive individuals. Int. J. Cancer 35: 35– 42.

132. Yates, J.,, N. Warren,, D. Reisman,, and B. Sugden. 1984. A cis-acting element from the Epstein-Barr viral genome that permits stable replication of recombinant piasmids in latently infected cells. Proc. Natl. Acad. Sci. USA 81: 3806– 3810.

133. Yates, J. L.,, and N. Guan. 1991. Epstein-Barr virus-derived piasmids replicate only once per cell cycle and are not amplified after entry into cells. J. Virol. 65: 483– 488.

134. Yates J. L.,, N. Warren,, and B. Sugden. 1985. Stable replication of plasmids derived from Epstein-Barr virus in various mammalian cells. Nature (London) 313: 812– 815.

135. Yoshida, M., 1994. Retroviruses (HTLVs), p. 929– 943. In G. Stamatoyannopoulos,, A. W. Nienhaus,, P. W. Majerus,, and H. Varmus (ed.), The Molecular Basis of Blood Diseases. The W. B. Saunders Co., Philadelphia.

136. Zhang, S.,, and M. Nonoyama. 1994. The cellular proteins that bind specifically to the Epstein-Barr virus origin of plasmid DNA replication belong to a gene family. Proc. Natl. Acad. Sci. USA 91: 2843– 2847.

137. Zimber-Strobl, U.,, E. Kremmer,, F. Grässer,, G. Marschall,, G. Laux,, and G. W. Bornkamm. 1993. The Epstein-Barr virus nuclear antigen 2 interacts with an EBNA2 responsive cis-element of the terminal protein 1 gene promoter. EMBO J. 12: 167– 175.