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Вопросы вирусологии. 2015; 60: 11-16

Роль консервативных и гипервариабельных иммунодоминантных эпитопов внутренних белков вирусов гриппа А в формировании цитотоксического Т-клеточного иммунного ответа

Найхин А. Н., Лосев И. В.

Аннотация

Цитотоксический Т-клеточный иммунитет имеет важное значение в предотвращении развития гриппозной инфекции и смягчении ее тяжести. Сведения о механизмах индукции вирусспецифических CD8+ Т-лимфоцитов (ВЦТЛ) у людей способствуют лучшему пониманию эпидемиологии гриппа и путей совершенствования его вакцинопрофилактики. В последние годы благодаря появлению новых иммунологических и генно-инженерных методик в мировой литературе накоплен материал об особенностях формирования ВЦТЛ-иммунного ответа к различным эпитопам внутренних белков вирусов гриппа А. В настоящем обзоре обобщены эти сведения. Основное внимание уделяется: (i) формированию гетеросубтипического ВЦТЛ-иммунного ответа к консервативным иммунодоминантным сайтам; (ii) механизмам ухода от контроля гриппозной инфекции хозяйскими ВЦТЛ с помощью эволюционных escape-мутаций; (iii) роли хозяйского HLA-гаплотипа на развитие этого типа иммунного ответа. Обсуждается важность цитируемых материалов для функциональной и прикладной иммунологии, а также для вакцинного дела.
Список литературы

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2. McMichael A.J., Gotch F.M., Noble G.R., Beare P.A. Cytotoxic T-cell immunity to influenza. N. Engl. J. Med. 1983; 309 (1): 13–7.

3. Yewdell J.W. Confronting complexity: real-world immunodominance in antiviral CD8+ T cell responses. Immunity. 2006; 25: 533–43.

4. Boon A.C., de Mutsert G., Graus Y.M., Fouchier R.A., Sintnicolaas K., Osterhaus A.D., Rimmelzwaan G.F. The magnitude and specificity of influenza A virus-specific cytotoxic T-lymphocyte responses in humans is related to HLA-A and –B phenotype. Virol. 2002; 76: 582- 590.

5. Chen W., Pang K., Masterman K.A. et al. Reversal in the immunodominance hierarchy in secondary CD8+ T cell responses to influenza A virus: roles for cross-presentation and lysis-independent immunodomination. J. Immunol. 2004; 173: 5021–7.

6. Belz G.T., Xie W., Doherty P.C. Diversity of epitope and cytokine profiles for primary and secondary influenza A virus-specific CD8+ T cell responses. J. Immunol. 2001; 166: 4627–33.

7. Boon A.C., de Mutsert G., Graus Y.M. et al. Sequence variation in a newly identified HLA-B35-restricted epitope in the influenza A virus nucleoprotein associated with escape from cytotoxic T lymphocytes. J. Virol. 2002; 76 (5): 2567–72.

8. Boon A.C., de Mutsert G., Fouchier R.A., Osterhaus A.D., Rimmelzwaan G.F. The hypervariable immunodominant NP418–426 epitope from the influenza A virus nucleoprotein is recognized by cytotoxic T lymphocytes with high functional avidity. J. Virol. 2006; 80 (12): 6024–32.

9. DiBrino M.T., Tsuchida T., Turner R.V. et al. An HLA-B35-restricted epitope modified at an anchor residue results in an antagonist peptide. Eur. J. Immunol. 1993; 26: 335–339.

10. Huet S., Nixon D.F., Rothbard J.B. Structural homologies between two HLA B27–restricted peptides suggests residues important for interaction with HLA B27. Int. Immunol. 1990; 2: 311–6.

11. McMichael A.J., Gotch F.M., Rothbard J. HLA B37 determines an influenza virus nucleoprotein epitope recognized by cytotoxic T lymphocytes. J. Exp. Med. 1986; 164: 1397–406.

12. Rimmelzwaan G.F., Kreijtz J.H., Bodewes R., Fouchier R.A., Osterhaus A.D. Influenza virus CTL epitopes, remarkably conserved and remarkably variable. Vaccine. 2009; 27: 6363–5.

13. Sutton J., Rowland-Jones S., Rosenberg W. et al. A sequence pattern for peptides presented to cytotoxic T lymphocytes by HLA B8 revealed by analysis of epitopes and eluted peptides. Eur. J. Immunol. 1993; 23: 447–453.

14. Heiny A.T., Miotto O., Srinivasan K.N., Khan A.M., Zhang G.L., Brusic V. et al. Evolutionarily conserved protein sequences of influenza A viruses, avian and human, as vaccine targets. PloS ONE (2007)./ www.plosone.org/ Issue 11/e1190.

15. Tan P.T., Heiny A.T., Miotto O., Salmon J., Marques E.T., Lemonnier F., August J.T.. Conservation and diversity of influenza A (H1N1) HLA-restricted T cell epitope candidates for epitope-based vaccines. PloS ONE (2010) / www.plosone.org/vol.5/Issue 1/e8754.

16. Voeten J.T.M., Bestebroer N.M., Nieuwkoop N.J., Fouchier R.A., Osterhaus A.D., Rimmelzwaan G.F. Antigenic drift in the influenza A virus (H3N2) nucleoprotein and escape from recognition by cytotoxic T lymphocytes. J. Virol. 2000; 74 (15): 6800–7.

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Problems of Virology. 2015; 60: 11-16

The impact of conservative and hypervariable immunodominant epitopes in internal proteins of the influenza A virus on cytotoxic T-cell immune responses

Naikhin A. N., Losev I. V.

Abstract

The cytotoxic T-cell immune response plays an important role in the prevention of influenza infection and reducing of the illness severity. The knowledge about mechanisms of the virus-specific CD8+ T-cell induction in humans is necessary for better understanding of influenza epidemiology and vaccine development. Due to application of new immunological and genetic methods in last years, considerable amount of data became available in the literature about CD8+ T-cell immune responses to different influenza A viruses. This review summarizes these data. The main attention is paid to (i) heterosubtypic CTL responses to conservative immunodominant sites; (ii) mechanisms of viral escape from the virus-specific CTLs by means of evolutional escape-mutations; (iii) influence of the HLA haplotype on CD8+ T-cell immune responses. The importance of these data for immunology and vaccinology is discussed.
References

1. Taylor P.M., Askonas B.A. Influenza nucleoprotein-specific cytotoxic T-cell clones are protective in vivo. Immunology. 1986; 58 (3): 417– 20.

2. McMichael A.J., Gotch F.M., Noble G.R., Beare P.A. Cytotoxic T-cell immunity to influenza. N. Engl. J. Med. 1983; 309 (1): 13–7.

3. Yewdell J.W. Confronting complexity: real-world immunodominance in antiviral CD8+ T cell responses. Immunity. 2006; 25: 533–43.

4. Boon A.C., de Mutsert G., Graus Y.M., Fouchier R.A., Sintnicolaas K., Osterhaus A.D., Rimmelzwaan G.F. The magnitude and specificity of influenza A virus-specific cytotoxic T-lymphocyte responses in humans is related to HLA-A and –B phenotype. Virol. 2002; 76: 582- 590.

5. Chen W., Pang K., Masterman K.A. et al. Reversal in the immunodominance hierarchy in secondary CD8+ T cell responses to influenza A virus: roles for cross-presentation and lysis-independent immunodomination. J. Immunol. 2004; 173: 5021–7.

6. Belz G.T., Xie W., Doherty P.C. Diversity of epitope and cytokine profiles for primary and secondary influenza A virus-specific CD8+ T cell responses. J. Immunol. 2001; 166: 4627–33.

7. Boon A.C., de Mutsert G., Graus Y.M. et al. Sequence variation in a newly identified HLA-B35-restricted epitope in the influenza A virus nucleoprotein associated with escape from cytotoxic T lymphocytes. J. Virol. 2002; 76 (5): 2567–72.

8. Boon A.C., de Mutsert G., Fouchier R.A., Osterhaus A.D., Rimmelzwaan G.F. The hypervariable immunodominant NP418–426 epitope from the influenza A virus nucleoprotein is recognized by cytotoxic T lymphocytes with high functional avidity. J. Virol. 2006; 80 (12): 6024–32.

9. DiBrino M.T., Tsuchida T., Turner R.V. et al. An HLA-B35-restricted epitope modified at an anchor residue results in an antagonist peptide. Eur. J. Immunol. 1993; 26: 335–339.

10. Huet S., Nixon D.F., Rothbard J.B. Structural homologies between two HLA B27–restricted peptides suggests residues important for interaction with HLA B27. Int. Immunol. 1990; 2: 311–6.

11. McMichael A.J., Gotch F.M., Rothbard J. HLA B37 determines an influenza virus nucleoprotein epitope recognized by cytotoxic T lymphocytes. J. Exp. Med. 1986; 164: 1397–406.

12. Rimmelzwaan G.F., Kreijtz J.H., Bodewes R., Fouchier R.A., Osterhaus A.D. Influenza virus CTL epitopes, remarkably conserved and remarkably variable. Vaccine. 2009; 27: 6363–5.

13. Sutton J., Rowland-Jones S., Rosenberg W. et al. A sequence pattern for peptides presented to cytotoxic T lymphocytes by HLA B8 revealed by analysis of epitopes and eluted peptides. Eur. J. Immunol. 1993; 23: 447–453.

14. Heiny A.T., Miotto O., Srinivasan K.N., Khan A.M., Zhang G.L., Brusic V. et al. Evolutionarily conserved protein sequences of influenza A viruses, avian and human, as vaccine targets. PloS ONE (2007)./ www.plosone.org/ Issue 11/e1190.

15. Tan P.T., Heiny A.T., Miotto O., Salmon J., Marques E.T., Lemonnier F., August J.T.. Conservation and diversity of influenza A (H1N1) HLA-restricted T cell epitope candidates for epitope-based vaccines. PloS ONE (2010) / www.plosone.org/vol.5/Issue 1/e8754.

16. Voeten J.T.M., Bestebroer N.M., Nieuwkoop N.J., Fouchier R.A., Osterhaus A.D., Rimmelzwaan G.F. Antigenic drift in the influenza A virus (H3N2) nucleoprotein and escape from recognition by cytotoxic T lymphocytes. J. Virol. 2000; 74 (15): 6800–7.

17. Wu K.-W., Chien C.-Y., Li S.-W., King C.-C., Chang C.-H. Highly conserved influenza A virus epitope sequences as candidates of H3N2 flu vaccine targets. Genomics. 2012; doi: 10.1016/j. ygeno.2012.06.003.

18. Marsh S., Parham P., Barber L. The HLA facts book. Academic Press, London. United Kingdom. 2000.

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20. Berkhoff E.G., Boon A.C., Nieuwkoop N.J., Fouchier R.A., Sintnicolaas K., Osterhaus A.D., Rimmelzwaan G.F. A mutation in the HLA-B82705-restricted NP383–391 epitope affects the human influenza A virus-specific cytotoxic T-lympocyte response in vitro. J. Virol. 2004; 78 (10): 5216–22.

21. Berkhoff E.G., de Wit E., Geelhoed-Mieras M.M., Boon A.C., Symons J., Fouchier R.A. et al. Functional constraints of influenza A virus epitopes limit escape from cytotoxic T lymphocytes. J. Virol. 2005; 79: 11 239–46.

22. Berkhoff E.G., Geelhoed-Mieras M.M., Fouchier R.A., Osterhaus A.D., Rimmelzwaan G.F. Assessment of the extent of variation in influenza A virus cytotoxic T-lymphocyte epitopes by using virusspecific CD8+ T-cell clones. J. General Virology. 2007; 88: 530–5.

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24. Naikhin A.N. Protivogrippoznyi immunitet: otechestvennyi vklad v izuchenie problemy i perspektivnye napravleniya razvitiya issledovanii. Med. akadem. zhurnal. 2010; 10 (4): 249–55. [Naykhin A.N. Anti-influenza immunity: the contribution of Russian scientists to the research work and promising directions. Med. Academic J. 2010; 10 (4): 249–55]. (in Russian)

25. Naikhin A.N., Chirkova T.V.. Petukhova G.D., Koren'kov D.A., Donina S.A., Rudenko L.G. Stimulyatsiya gomo- i geterologicheskoi T-kletochnoi immunologicheskoi pamyati u volonterov, privitykh zhivoi reassortantnoi grippoznoi vaktsinoi tipa A(N5N2). Voprosy virusologii. 2012; 1: 38–42. [Naikhin A.N., Chirkova T.V., Petukhova G.D., Korenkov D.A., Donina S.A., Rudenko L.G. Stimulation of homo- and heterologic T-cell immunological memory in volunteers inoculated with live influenza A (H5N2) reassortant vaccine. Voprosy virusologii. 2012; 1: 38–42]. (in Russian)

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27. Epstein S.L. Prior H1N1 influenza infection and susceptibility of Cleveland Family Study participants during the H2N2 pandemic of 1957: an experiment of nature. J. Infect. Dis. 2006; 193 (1): 49–53.

28. Grebe K.M., Yewdell J.W., Bennink J.R. Heterosubtypic immunity to influenza A virus: where do we stend? Microbes Infect. 2008; 10 (July (9)): 1024–9.

29. Kreijtz J.H., Bodewes R., van Amerongen G. et al. Primary influenza A virus infection induces cross-protective immunity against a lethal infection with a heterosubtypic virus strain in mice. Vaccine. 2007; 25 (January(4)): 612–20.

30. Kreijtz J.H., de Mutsert G., van Baalen C.A. et al. Cross-recognition of avian H5N1 influenza virus by human cytotoxic T-lymphocyte populations directed to human influenza A virus. J. Virol. 2008; 82 (11): 5161–6.

31. Koup R.A. Virus escape from CTL recognition. J. Exp. Med. 1994; 180: 779–82.

32. Oldstone M.B. How viruses escape from cytotoxic T lymphocytes: molecular parameters and players. Virology. 1997; 234: 179–85.

33. Borrow P., Lewicki H., Wei X. et al. Antiviral pressure exerted by HIV-I-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus. Nat. Med. 1997; 3: 205–11.

34. Jugovic P., Hill A.M., Tomazin R. et al. Inhibition of major histocompatibility complex class I antigen presentation in pig and primate cells by herpes simplex virus type 1 and 2 ICP47. J. Virol. 1998; 72: 5076–84.

35. Khanna R., Burrows S.R., Argaet V., Moss D.J. Endoplasmie reticulum signal sequence facilitated transport of peptide epitopes restores immunogenicity of an antigen processing defective tumour cell line. Int. Immunol. 1994; 6: 639–45.

36. Moskophidis D., Zinkernagel R.M. Immunobiology of cytotoxic Tcell escape mutants of lymphocytic choriomeningitis virus. J. Virol. 1995; 69: 2187–93.

37. Pircher H.D., Moskophidis D., Rohrer U. et al. Viral escape by selection of cytotoxic T cell-resistant virus variants in vivo. Nature. 1990; 346: 629–33.

38. Bertoletti A., Costanzo A., Chisari F.V. et al. Cytotoxic T lymphocyte response to a wild type hepatitis B virus epitope in patients chronically infected by variant viruses carrying substitutions within the epitope. J. Exp. Med. 1994; 180: 933–43.

39. Bertoletti A., Sette A., Chisari F.V. et al. Natural variants of cytotoxic epitopes are T-cell receptor antagonists for antiviral cytotoxic T cells. Nature. 1994; 369: 407–10.

40. Borrows J.M., Borrows S.R., Poulsen L.M. et al. Unusually high frequency of Epstein-Barr virus genetic variants in Papua New Guinea that can escape cytotoxic T-cell recognition: implications for virus evolution. J. Virol. 1996; 70: 2490–6.

41. de Campos-Lima P.O., Levitsky V., Brooks J. et al. T cell responses and virus evolution: loss of HLA A11-restricted CTL epitopes in EpsteinBarr virus isolates from highly A11-positive populations by selective mutation of anchor residues. J. Exp. Med. 1994; 179: 1297–305.

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