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

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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.

About the authors

A. N. Naikhin

Institute of Experimental Medicine, Russian Academy of Medical Sciences

Author for correspondence.
Email: vaccine@mail.ru

Anatoliy Naykhin, MD, PhD, DSc, Prof.

197376, St. Petersburg

Россия

I. V. Losev

Institute of Experimental Medicine, Russian Academy of Medical Sciences

Email: fake@neicon.ru
197376, St. Petersburg Россия

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.
  19. Assarsson E., Bui H.-H., Sidney J., Zhang Q., Glenn J., Oseroff C. et al. Immunomic analysis of the repertoire of T-cell specificites for influenza A virus in humans. J. Virol. 2008; 82 (24): 12 241–51.
  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.
  23. Stanekova Z., Vareckova E. Conserved epitopes of influenza A virus inducing protective immunity and their prospects for universal vaccine development. Virology J. 2010; 7: 351.
  24. Найхин А.Н. Противогриппозный иммунитет: отечественный вклад в изучение проблемы и перспективные направления развития исследований. Мед. академ. журнал. 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. Найхин А.Н., Чиркова Т.В.. Петухова Г.Д., Кореньков Д.А., Донина С.А., Руденко Л.Г. Стимуляция гомо- и гетерологической Т-клеточной иммунологической памяти у волонтеров, привитых живой реассортантной гриппозной вакциной типа А(Н5N2). Вопросы вирусологии. 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)
  26. Найхин А.Н. Гетеросубтипический иммунитет к вирусам гриппа А: эпидемиологические данные, вовлеченность разных иммунологических факторов, вакцинация. Вопросы вирусологии. 2012; 57 (3): 4–9. [Naikhin A.N. Heterosubtypic immunity to influenza A viruses: epidemiological data, involvement of different immunological factors, vaccination. Voprosy virusologii. 2012; 57 (3): 4–9]. (in Russian)
  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.
  42. Guglietta S., Garbuglia A.R., Pacciani et al. Positive selection of cytotoxic T lymphocyte escape variants during acute hepatitis C virus infection. Eur. J. Immunol. 2005; 35: 2627–37.
  43. Man S., Newbery H., Crotzer V.l. et al. Definition of human T cell epitope from influenza A non-structural protein 1 using HLA-A21 transgenic mice. Inf. Immunol. 1995; 7: 597–605.
  44. Rimmelzwaan G.F., Fouchier R.A., Osterhaus A. Influenza virusspecific cytotoxic T lymphocytes: a correlate of protection and a basis for vaccine development. Current Opinion in Biotechnology. 2007; 18: 529–36.
  45. Ploegh H.L. Viral strategies of immune evasion. Science. 1998; 280: 248–53.
  46. Boon A.C., de Mutsert G., van Baarle D., Smith D.J., Lapedes A.S., Fouchier R.A. et al. Recognition of homo- and heterosubtypic variants of influenza A viruses by human CD8+ T lymphocytes. J. Immunol. 2004; 172: 2453–60.
  47. Portela A., Digard Р. The influenza virus nucleoprotein: a multifunctional RNA-binding protein pivotal to virus replication. J. Gen. Virol. 2002; 83 (April (Pt 4)): 723–34.
  48. Gog J.R., Rimmelzwaan G.F., Osterhaus A.D. Grenfell B.T. Population dynamics of rapid fixation in cytotoxic T lymphocyte escape mutants of influenza A. PNAS. 2003; 100 (19): 11 143–7.
  49. Macken C., Lu H., Goodman J., Boykin L. The value of a database in surveillance and vaccine selection. Options for the control of influenza IV. Elsevier Science. Amsterdam. The Netherlands, 2001: 103–6.
  50. Rimmelzwaan G.F., Berkhoff E.G., Nieuwkoop N. J. et al. Functional compensation of a detrimental amino acid substitution in a cytotoxic-T-lymphocyte epitope of influenza A viruses by comutations. J. Virolog. 2004; 78 (16): 8946–9.
  51. Rimmelzwaan G.F., Berkhoff E.G., Nieuwkoop N.J., Smith D.J., Fouchier R.A., Osterhaus A.D. Full restoration of viral fitness by multiple compensatory co-mutations in the nucleoprotein of influenza A virus cytotoxic T-lymphocyte escape mutants. J. General Virology. 2005; 86: 1801–5.
  52. Alexander-Miller M.A. High-avidity Cd8+ T cell: optimal soldiers in the war against viruses and tumors. Immonol. Res. 2005; 31: 13–24.
  53. Derby M., Alexander-Miller M., Tse R., Berzofsky J. High-avidity CTL exploit two complementary mechanisms to provide better protection against viral infection than low-avidity CTL. J. Immunol. 2001; 166: 1690–7.
  54. O’Connor D.H., Allen T.M., Vogel T.U. et al. Acute phase cytotoxic T lymphocyte escape is a hallmark of simian immunodeficiency virus infection. Nat. Med. 2002; 8: 493–9.
  55. Zeh H.J., Perry-Lalley III.D., Dudley M.E. High-avidity CTLs for two self-antigens demonstrate superior in vitro and in vivo antitumor efficacy. J. Immunol. 1999; 162: 989–94.
  56. Berkhoff E.G., Geelhoed-Mieras M.M., Verschuren E.J., Baalen C.A., Gruters R.A., Fouchier R.A., Osterhaus A.D., Rimmelzwaan G.F. The loss of immunodominant epitopes affects interferon-γ production and lytic activity of the human influenza virus-specific cytotoxic T lymphocyte response in vitro. J. Clinical and Exp. Immunol. 2007; 148: 296–306.
  57. Bodewes R., Geelhoed-Mieras M.M., Nieuwkoop N.J., Hanson J.A., David C.S., Fouchier R.A., Osterhaus A.D., Rimmelzwaan G.F. Redundancy of the influenza A virus-specific cytotoxic T lymphocyte response in HLA-B*2705 transgenic mice limits the impact of a mutation in the immunodominant NP383–391 epitope on influenza pathogenesis. Virus Research. 2011; 155: 123–30.
  58. Carrat F., Flahault F. Influenza vaccine: The challenge of antigenic drift. Vaccine. 2007; 25: 6852–62.
  59. EIhefnawi M., ALAidi O., Mohamed N., Kamar M., EI-Azab I., Zaba S., Siam R. Identification of novel conserved functional motifs across most influenza A viral strains. Virology J. 2011; 8: 44.
  60. Li C., Rappuoli R., Xu X.-N. Correlates of protection against influenza infection in humans – on the path to a universal vaccine? Current Opinion in Immunology. 2013; 25: 470–6.

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