Вопросы вирусологии. 2022; 67: 246-257
Вирус Эпштейна–Барр (Herpesviridae: Gammaherpesvirinae: Lymphocryptovirus: Human gammaherpesvirus 4) у калмыков и славян, проживающих на территории России: типы вируса, варианты онкогена LMP1 и злокачественные опухоли
https://doi.org/10.36233/0507-4088-120Аннотация
Введение. Открытие типов вируса Эпштейна–Барр (Herpesviridae: Gammaherpesvirinae: Lymphocryptovirus: Human gammaherpesvirus 4) (ВЭБ) – ВЭБ-1 и ВЭБ-2, обладающих различной трансформирующей способностью in vitro, стимулировало изучение их распространённости в популяциях с целью выяснения связи со злокачественными новообразованиями.
Цели работы – изучение распространённости ВЭБ-1 и ВЭБ-2 у представителей 2 этносов России, калмыков и славян, сиквенсный анализ онкогена LMP1 в изолятах вируса и анализ корреляции между типами вируса и заболеваемостью определенными формами опухолей.
Материалы и методы. Из биологического материала смывов полости рта, полученных от этнических калмыков Республики Калмыкия (РК) (n = 50) и славян, жителей Московской области (МО) (n = 40), выделяли образцы ДНК. Последние использовали для амплификации ДНК ВЭБ, с последующим определением её концентрации на 1 клетку смыва, амплификацией в вирусных образцах онкогена LMP1, их секвенированием и определением белковых вариантов LMP1.
Результаты. Установлено, что при одинаковой нагрузке ВЭБ среди представителей обоих этносов в группе калмыков соотношение лиц, инфицированных трансформирующим и нетрансформирующим типами вирса, было практически одинаковым (ВЭБ-1 – 51%; и ВЭБ-2 – 49%), а в группе славян доминировал трансформирующий тип ВЭБ-1 (80,6%). Доминантное инфицирование представителей славян 1-м типом вируса (ВЭБ-1) коррелировало с повышенными показателями заболеваемости некоторыми формами опухолей у населения МО при сравнении с аналогичными показателями у населения РК, представители которой инфицированы обоими типами вируса. Различия между сравниваемыми показателями онкозаболеваемости не были статистически значимыми. Анализ вирусных изолятов показал близкий набор вариантов LMP1 у обеих этнических групп.
Заключение. С целью установления влияния типов ВЭБ на заболеваемость злокачественными новообразованиями необходимы дополнительные исследования с участием представителей различных этнических групп из разных географических регионов.
Список литературы
1. Davison A.J., Eberle R., Ehlers B., Hayward G.S., McGeoch D.J., Minson A.C., et al. The order Herpesvirales. Arch. Virol. 2009; 154(1): 171–7. https://doi.org/10.1007/s00705-008-0278-4
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6. Sample J., Young L., Martin B., Chatman T., Kieff E., Rickinson A., et al. Epstein–Barr virus types 1 and 2 differ in their EBNA-3A, EBNA-3B, and EBNA-3C genes. J. Virol. 1990; 64(9): 4084–92. https://doi.org/10.1128/JVI.64.9.4084-4092.1990
7. Gratama J.W., Ernberg I. Molecular epidemiology of Epstein–Barr virus infection. Adv. Cancer Res. 1995; 67: 197–255.
8. Coleman C.B., Wohlford E.M., Smith N.A., King C.A., Ritchie J.A., Baresel P.C., et al. Epstein–Barr virus type 2 latently infects T cells, inducing an atypical activation characterized by expression of lymphotactic cytokines. J. Virol. 2015; 89(4): 2301–12. https://doi.org/10.1128/JVI.03001-14
9. Kaymaz Y., Oduor C.I., Yu H., Otieno J.A., Ong’echa J.M., Moormann A.M., et al. Comprehensive transcriptome and mutational profiling of endemic Burkitt lymphoma reveals EBV type-specific differences. Mol. Cancer Res. 2017; 15(5): 563–76. https://doi.org/10.1158/1541-7786.MCR-16-0305
10. Bentz G.L., Whitehurst C.B., Pagano J.S. Epstein–Barr virus latent membrane protein 1 (LMP1) C-terminal-activating region 3 contributes to LMP1-mediated cellular migration via its interaction with Ubc9. J. Virol. 2011; 85(19): 10144–53. https://doi.org/10.1128/JVI.05035-11
11. Li H.P., Chang Y.S. Epstein–Barr virus latent membrane protein 1: structure and functions. J. Biomed. Sci. 2003; 10(5): 490–504. https://doi.org/10.1007/BF02256110
12. Dawson C.W., Port R.J., Young L.S. The role of the EBV-encoded latent membrane proteins LMP1 and LMP2 in the pathogenesis of nasopharyngeal carcinoma (NPC). Semin. Cancer Biol. 2012; 22(2): 144–53. https://doi.org/10.1016/j.semcancer.2012.01.004
13. Edwards R.H., Seillier-Moiseiwitsch F., Raab-Traub N. Signature amino acid changes in latent membrane protein 1 distinguish Epstein–Barr virus strains. Virology. 1999; 261(1): 79–95. https://doi.org/10.1006/viro.1999.9855
14. Saechan V., Settheetham-Ishida W., Kimura R., Tiwawech D., Mitarnun W., Ishida T. Epstein–Barr virus strains defined by the latent membrane protein 1 sequence characterize Thai ethnic groups. J. Gen. Virol. 2010; 91(Pt. 8): 2054–61. https://doi.org/10.1099/vir.0.021105-0
15. Saechan V., Mori A., Mitarnun W., Settheetham-Ishida W., Ishida T. Analysis of LMP1 variants of EBV in Southern Thailand: evidence for strain-associated T-cell tropism and pathogenicity. J. Clin. Virol. 2006; 36(2): 119–25. https://doi.org/10.1016/j.jcv.2006.01.018
16. Gantuz M., Lorenzetti M.A., Chabay P.A., Preciado M.V. A novel recombinant variant of latent membrane protein 1 from Epstein Barr virus in Argentina denotes phylogeographical association. PLoS One. 2017; 12(3): e0174221. https://doi.org/10.1371/journal.pone.0174221
17. Burrows J.M., Bromham L., Woolfit M., Piganeau G., Tellam J., Connolly G., et al. Selection pressure-driven evolution of the Epstein–Barr virus-encoded oncogene LMP1 in virus isolates from Southeast Asia. J. Virol. 2004; 78(13): 7131–7. https://doi.org/10.1128/JVI.78.13.7131-7137.2004
18. Lin H.J., Cherng J.M., Hung M.S., Sayion Y., Lin J.C. Functional assays of HLA A2-restricted epitope variant of latent membrane protein 1 (LMP-1) of Epstein–Barr virus in nasopharyngeal carcinoma of Southern China and Taiwan. J. Biomed. Sci. 2005; 12(6): 925–36. https://doi.org/10.1007/s11373-005-9017-y
19. Smirnova K.V., Senyuta N.B., Botezatu I.V., Dushenkina T.E., Lubenskaya A.K., Frolovskaya A.A., et al. Epstein–Barr virus in the ethnic Tatars population: the infection and sequence variants of LMP1 oncogene. Успехи молекулярной онкологии. 2018; 5(3): 65–74. https://doi.org/10.17650/2313-805X-2018-5-3-65-74.
20. Hahn P., Novikova E., Scherback L., Janik C., Pavlish O., Arkhipov V., et al. The LMP1 gene isolated from Russian nasopharyngeal carcinoma has no 30-bp deletion. Int. J. Cancer. 2001; 91(6): 815–21. https://doi.org/10.1002/1097-0215(200002)9999:9999<::aid-ijc1122>3.0.co;2-w
21. Salahuddin S., Khan J., Azhar J., Khan J., Muhammad N. Prevalence of Epstein–Barr virus genotypes in Pakistani lymphoma patients. Asian Pac. J. Cancer Prev. 2018; 19: 3153–9. https://doi.org/10.31557/APJCP.2018.19.11.3153
22. Lo Y.M., Chan L.Y., Chan A.T., Leung S.F., Lo K.W., Zhang J. Quantitative and temporal correlation between circulating cell-free Epstein–Barr virus DNA and tumor recurrence in nasopharyngeal carcinoma. Cancer Res. 1999; 59(21): 5452–5.
23. Lawrence J.B., Villnave C.A., Singer R.H. Sensitive, high-resolution chromatin and chromosome mapping in situ: presence and orientation of two closely integrated copies of EBV in a lymphoma line. Cell. 1988; 52(1): 51–61. https://doi.org/10.1016/0092-8674(88)90530-2
24. Botezatu I.V., Kondratova V.N., Shelepov V.P., Lichtenstein A.V. DNA melting analysis: application of the “open tube” format for detection of mutant KRAS. Anal. Biochem. 2011; 419(2): 302–8. https://doi.org/10.1016/j.ab.2011.08.015
25. Смирнова К.В., Дидук С.В., Сенюта Н.Б., Гурцевич В.Э. Молекулярно-биологические свойства гена LMP1 вируса Эпштейна–Барр: структура, функции и полиморфизм. Вопросы вирусологии. 2015; 60(3): 5–13.
26. Scheinfeld A.G., Nador R.G., Cesarman E., Chadburn A., Knowles D.M. Epstein–Barr virus latent membrane protein-1 oncogene deletion in post-transplantation lymphoproliferative disorders. Am. J. Pathol. 1997; 151(3): 805–12.
27. Miller W.E., Edwards R.H., Walling D.M., Raab-Traub N. Sequence variation in the Epstein–Barr virus latent membrane protein 1. J. Gen. Virol. 1994; 75(Pt. 10): 2729–40. https://doi.org/10.1099/0022-1317-75-10-2729
28. Kanai K., Satoh Y., Saiki Y., Ohtani H., Sairenji T. Difference of Epstein–Barr virus isolates from Japanese patients and African Burkitt’s lymphoma cell lines based on the sequence of latent membrane protein 1. Virus Genes. 2007; 34(1): 55–61. https://doi.org/10.1007/s11262-006-0010-y
29. Senyuta N., Yakovleva L., Goncharova E., Scherback L., Diduk S., Smirnova K., et al. Epstein–barr virus latent membrane protein 1 polymorphism in nasopharyngeal carcinoma and other oral cavity tumors in Russia. J. Med. Virol. 2014; 86(2): 290–300. https://doi.org/10.1002/jmv.23729
30. Schuster V., Ott G., Seidenspinner S., Kreth H.W. Common Epstein–Barr virus (EBV) type-1 variant strains in both malignant and benign EBV-associated disorders. Blood. 1996; 87(4): 1579–85.
31. Khanim F., Yao Q.Y., Niedobitek G., Sihota S., Rickinson A.B., Young L.S. Analysis of Epstein–Barr virus gene polymorphisms in normal donors and in virus-associated tumors from different geographic locations. Blood. 1996; 88(9): 3491–501.
32. Лубенская А.К., Сенюта Н.Б., Ботезату И.В., Душенькина Т.Е., Лихтенштейн А.В., Гурцевич В.Э., Смирнова К.В. Вирус Эпштейна–Барр у адыгейцев и славян в России: типы вируса, варианты LMP1 и злокачественные новообразования. Материалы VI Всероссийской конференции по молекулярной онкологии, 21–23 декабря 2021 г., Москва. Успехи молекулярной онкологии. 2021; 4(8): 96–97.
Problems of Virology. 2022; 67: 246-257
Epstein–Barr virus (Herpesviridae: Gammaherpesvirinae: Lymphocryptovirus: Human gammaherpesvirus 4) in Kalmyks and Slavs living in Russia: virus types, LMP1 oncogene variants, and malignancies
https://doi.org/10.36233/0507-4088-120Abstract
Introduction. The discovery of the Epstein-Barr virus types (Herpesviridae: Gammaherpesvirinae: Lymphocryptovirus: Human gammaherpesvirus 4) (EBV) – EBV-1 and EBV-2, which have different transforming abilities in vitro, stimulated the study of their prevalence in populations in order to elucidate the relationship with malignant neoplasms.
The aims of the work are to study the prevalence of EBV-1 and EBV-2 among representatives of 2 ethnic groups of Russia, Kalmyks and Slavs, sequencing analysis of the LMP1 oncogene in virus isolates, and analysis of the correlation between virus types and the incidence of certain forms of tumors.
Materials and methods. DNA samples were isolated from the biological material of oral swabs obtained from ethnic Kalmyks of the Republic of Kalmykia (RK) (n = 50) and Slavs, residents of the Moscow Region (MR) (n = 40). DNA samples were used to amplify EBV DNA, followed by determination of its concentration per 1 cell of washout, amplification of the LMP1 oncogene in viral samples, their sequencing, and determination of LMP1 protein variants.
Results. It has been established that with the same burden of EBV among representatives of both ethnic groups in the Kalmyk group, the ratio of persons infected with transforming and non-transforming types of the virus was almost the same (EBV-1 – 51%; and EBV-2 – 49%). Meanwhile, in the group of Slavs the transforming EBV-1 type virus dominated (80.6%). The predominance of EBV-1 type in representatives of the Slavs correlated with increased incidence of certain forms of tumors in the population of the MR when compared with similar values in the population of the RK, where both types of the virus were prevalent. Differences between the compared rates of cancer incidence were not statistically significant. Analysis of viral isolates showed a similar set of LMP1 variants in both ethnic groups.
Conclusion. In order to establish the influence of EBV types on the incidence of malignant tumors, additional studies involving representatives of various ethnic groups from different geographical regions are needed.
References
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2. Dolan A., Addison C., Gatherer D., Davison A.J., McGeoch D.J. The genome of Epstein–Barr virus type 2 strain AG876. Virology. 2006; 350(1): 164–70. https://doi.org/10.1016/j.virol.2006.01.015
3. Young L.S., Rickinson A.B. Epstein–Barr virus: 40 years on. Nat. Rev. Cancer. 2004; 4(10): 757–68. https://doi.org/10.1038/nrc1452
4. Moore P.S., Chang Y. Why do viruses cause cancer? Highlights of the first century of human tumour virology. Nat. Rev. Cancer. 2010; 10(12): 878–89. https://doi.org/10.1038/nrc2961
5. McGeoch D.J. Molecular evolution of the γ–Herpesvirinae. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2001; 356(1408): 421–35. https://doi.org/10.1098/rstb.2000.0775
6. Sample J., Young L., Martin B., Chatman T., Kieff E., Rickinson A., et al. Epstein–Barr virus types 1 and 2 differ in their EBNA-3A, EBNA-3B, and EBNA-3C genes. J. Virol. 1990; 64(9): 4084–92. https://doi.org/10.1128/JVI.64.9.4084-4092.1990
7. Gratama J.W., Ernberg I. Molecular epidemiology of Epstein–Barr virus infection. Adv. Cancer Res. 1995; 67: 197–255.
8. Coleman C.B., Wohlford E.M., Smith N.A., King C.A., Ritchie J.A., Baresel P.C., et al. Epstein–Barr virus type 2 latently infects T cells, inducing an atypical activation characterized by expression of lymphotactic cytokines. J. Virol. 2015; 89(4): 2301–12. https://doi.org/10.1128/JVI.03001-14
9. Kaymaz Y., Oduor C.I., Yu H., Otieno J.A., Ong’echa J.M., Moormann A.M., et al. Comprehensive transcriptome and mutational profiling of endemic Burkitt lymphoma reveals EBV type-specific differences. Mol. Cancer Res. 2017; 15(5): 563–76. https://doi.org/10.1158/1541-7786.MCR-16-0305
10. Bentz G.L., Whitehurst C.B., Pagano J.S. Epstein–Barr virus latent membrane protein 1 (LMP1) C-terminal-activating region 3 contributes to LMP1-mediated cellular migration via its interaction with Ubc9. J. Virol. 2011; 85(19): 10144–53. https://doi.org/10.1128/JVI.05035-11
11. Li H.P., Chang Y.S. Epstein–Barr virus latent membrane protein 1: structure and functions. J. Biomed. Sci. 2003; 10(5): 490–504. https://doi.org/10.1007/BF02256110
12. Dawson C.W., Port R.J., Young L.S. The role of the EBV-encoded latent membrane proteins LMP1 and LMP2 in the pathogenesis of nasopharyngeal carcinoma (NPC). Semin. Cancer Biol. 2012; 22(2): 144–53. https://doi.org/10.1016/j.semcancer.2012.01.004
13. Edwards R.H., Seillier-Moiseiwitsch F., Raab-Traub N. Signature amino acid changes in latent membrane protein 1 distinguish Epstein–Barr virus strains. Virology. 1999; 261(1): 79–95. https://doi.org/10.1006/viro.1999.9855
14. Saechan V., Settheetham-Ishida W., Kimura R., Tiwawech D., Mitarnun W., Ishida T. Epstein–Barr virus strains defined by the latent membrane protein 1 sequence characterize Thai ethnic groups. J. Gen. Virol. 2010; 91(Pt. 8): 2054–61. https://doi.org/10.1099/vir.0.021105-0
15. Saechan V., Mori A., Mitarnun W., Settheetham-Ishida W., Ishida T. Analysis of LMP1 variants of EBV in Southern Thailand: evidence for strain-associated T-cell tropism and pathogenicity. J. Clin. Virol. 2006; 36(2): 119–25. https://doi.org/10.1016/j.jcv.2006.01.018
16. Gantuz M., Lorenzetti M.A., Chabay P.A., Preciado M.V. A novel recombinant variant of latent membrane protein 1 from Epstein Barr virus in Argentina denotes phylogeographical association. PLoS One. 2017; 12(3): e0174221. https://doi.org/10.1371/journal.pone.0174221
17. Burrows J.M., Bromham L., Woolfit M., Piganeau G., Tellam J., Connolly G., et al. Selection pressure-driven evolution of the Epstein–Barr virus-encoded oncogene LMP1 in virus isolates from Southeast Asia. J. Virol. 2004; 78(13): 7131–7. https://doi.org/10.1128/JVI.78.13.7131-7137.2004
18. Lin H.J., Cherng J.M., Hung M.S., Sayion Y., Lin J.C. Functional assays of HLA A2-restricted epitope variant of latent membrane protein 1 (LMP-1) of Epstein–Barr virus in nasopharyngeal carcinoma of Southern China and Taiwan. J. Biomed. Sci. 2005; 12(6): 925–36. https://doi.org/10.1007/s11373-005-9017-y
19. Smirnova K.V., Senyuta N.B., Botezatu I.V., Dushenkina T.E., Lubenskaya A.K., Frolovskaya A.A., et al. Epstein–Barr virus in the ethnic Tatars population: the infection and sequence variants of LMP1 oncogene. Uspekhi molekulyarnoi onkologii. 2018; 5(3): 65–74. https://doi.org/10.17650/2313-805X-2018-5-3-65-74.
20. Hahn P., Novikova E., Scherback L., Janik C., Pavlish O., Arkhipov V., et al. The LMP1 gene isolated from Russian nasopharyngeal carcinoma has no 30-bp deletion. Int. J. Cancer. 2001; 91(6): 815–21. https://doi.org/10.1002/1097-0215(200002)9999:9999<::aid-ijc1122>3.0.co;2-w
21. Salahuddin S., Khan J., Azhar J., Khan J., Muhammad N. Prevalence of Epstein–Barr virus genotypes in Pakistani lymphoma patients. Asian Pac. J. Cancer Prev. 2018; 19: 3153–9. https://doi.org/10.31557/APJCP.2018.19.11.3153
22. Lo Y.M., Chan L.Y., Chan A.T., Leung S.F., Lo K.W., Zhang J. Quantitative and temporal correlation between circulating cell-free Epstein–Barr virus DNA and tumor recurrence in nasopharyngeal carcinoma. Cancer Res. 1999; 59(21): 5452–5.
23. Lawrence J.B., Villnave C.A., Singer R.H. Sensitive, high-resolution chromatin and chromosome mapping in situ: presence and orientation of two closely integrated copies of EBV in a lymphoma line. Cell. 1988; 52(1): 51–61. https://doi.org/10.1016/0092-8674(88)90530-2
24. Botezatu I.V., Kondratova V.N., Shelepov V.P., Lichtenstein A.V. DNA melting analysis: application of the “open tube” format for detection of mutant KRAS. Anal. Biochem. 2011; 419(2): 302–8. https://doi.org/10.1016/j.ab.2011.08.015
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27. Miller W.E., Edwards R.H., Walling D.M., Raab-Traub N. Sequence variation in the Epstein–Barr virus latent membrane protein 1. J. Gen. Virol. 1994; 75(Pt. 10): 2729–40. https://doi.org/10.1099/0022-1317-75-10-2729
28. Kanai K., Satoh Y., Saiki Y., Ohtani H., Sairenji T. Difference of Epstein–Barr virus isolates from Japanese patients and African Burkitt’s lymphoma cell lines based on the sequence of latent membrane protein 1. Virus Genes. 2007; 34(1): 55–61. https://doi.org/10.1007/s11262-006-0010-y
29. Senyuta N., Yakovleva L., Goncharova E., Scherback L., Diduk S., Smirnova K., et al. Epstein–barr virus latent membrane protein 1 polymorphism in nasopharyngeal carcinoma and other oral cavity tumors in Russia. J. Med. Virol. 2014; 86(2): 290–300. https://doi.org/10.1002/jmv.23729
30. Schuster V., Ott G., Seidenspinner S., Kreth H.W. Common Epstein–Barr virus (EBV) type-1 variant strains in both malignant and benign EBV-associated disorders. Blood. 1996; 87(4): 1579–85.
31. Khanim F., Yao Q.Y., Niedobitek G., Sihota S., Rickinson A.B., Young L.S. Analysis of Epstein–Barr virus gene polymorphisms in normal donors and in virus-associated tumors from different geographic locations. Blood. 1996; 88(9): 3491–501.
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