tetano
Editor, Senior Moderator
J Virol. 2015 Nov 4. pii: JVI.02439-15. [Epub ahead of print]
[h=1]Differential recognition of influenza A viruses by M158-66 epitope-specific CD8+ T cells is determined by extra-epitopic amino acid residues.[/h] van de Sandt CE[SUP]1[/SUP], Kreijtz JH[SUP]1[/SUP], Geelhoed-Mieras MM[SUP]1[/SUP], Nieuwkoop NJ[SUP]1[/SUP], Spronken MI[SUP]1[/SUP], van de Vijver DA[SUP]1[/SUP], Fouchier RA[SUP]1[/SUP], Osterhaus AD[SUP]2[/SUP], Rimmelzwaan GF[SUP]3[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Natural influenza A virus infections elicit both virus-specific antibody and CD4[SUP]+[/SUP] and CD8[SUP]+[/SUP] T cell responses. Influenza A virus-specific CD8[SUP]+[/SUP] cytotoxic T lymphocytes (CTLs) contribute to clearance of influenza virus infections. Viral CTL epitopes can display variation, allowing influenza A viruses to evade from recognition by epitope-specific CTLs. Due to functional constraints, some epitopes, like the immunodominant HLA-A*0201 restricted matrix protein 1 (M1)[SUB]58-66[/SUB] epitope, are highly conserved between influenza A viruses regardless of their subtype or host species of origin. We hypothesized that human influenza A viruses evade recognition of this epitope by impairing antigen processing and presentation by extra-epitopic amino acid substitutions. Activation of specific T cells was used as read out for antigen presentation. Here, we show that the M1[SUB]58-66[/SUB] epitope in the M1 protein derived from human influenza A virus was poorly recognized compared to the M1 protein derived from avian influenza A virus. Furthermore, we demonstrated that naturally occurring variation at extra-epitopic amino acid residues affect CD8[SUP]+[/SUP] T cell recognition of the M1[SUB]58-66[/SUB] epitope. These data indicate that human influenza A viruses can impair recognition by M1[SUB]58-66[/SUB]-specific CTLs, while retaining the conserved amino acid sequence of the epitope, which may represent a yet unknown immune evasion strategy for influenza A viruses. This difference in recognition may have implications for the viral replication kinetics in HLA-A*0201 individuals and spread of influenza A viruses in the human population. The findings may aid the rational design of universal influenza vaccines that aim at the induction of cross-reactive virus-specific CTL responses.
[h=4]IMPORTANCE:[/h] Influenza viruses are an important cause of acute respiratory tract infections. Natural influenza A virus infections elicit both humoral and cellular immunity. CD8[SUP]+[/SUP] cytotoxic T lymphocytes (CTLs) are directed predominantly against conserved internal proteins and confer cross-protection, even against influenza A viruses of various subtypes. In some CTL epitopes mutations occur that allow influenza A viruses to evade from recognition by CTLs. However, the immunodominant HLA-A*0201 restricted M1[SUB]58-66[/SUB] epitope does not tolerate mutations without loss of viral fitness. Here, we describe naturally occurring variations in amino acid residues outside the M1[SUB]58-66[/SUB] epitope that influence the recognition of the epitope. These results provide novel insights in the epidemiology of influenza A viruses and their pathogenicity and may aid rational design of vaccines that aim at the induction of CTL responses.
Copyright ? 2015, American Society for Microbiology. All Rights Reserved.
PMID: 26537686 [PubMed - as supplied by publisher]
[h=1]Differential recognition of influenza A viruses by M158-66 epitope-specific CD8+ T cells is determined by extra-epitopic amino acid residues.[/h] van de Sandt CE[SUP]1[/SUP], Kreijtz JH[SUP]1[/SUP], Geelhoed-Mieras MM[SUP]1[/SUP], Nieuwkoop NJ[SUP]1[/SUP], Spronken MI[SUP]1[/SUP], van de Vijver DA[SUP]1[/SUP], Fouchier RA[SUP]1[/SUP], Osterhaus AD[SUP]2[/SUP], Rimmelzwaan GF[SUP]3[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Natural influenza A virus infections elicit both virus-specific antibody and CD4[SUP]+[/SUP] and CD8[SUP]+[/SUP] T cell responses. Influenza A virus-specific CD8[SUP]+[/SUP] cytotoxic T lymphocytes (CTLs) contribute to clearance of influenza virus infections. Viral CTL epitopes can display variation, allowing influenza A viruses to evade from recognition by epitope-specific CTLs. Due to functional constraints, some epitopes, like the immunodominant HLA-A*0201 restricted matrix protein 1 (M1)[SUB]58-66[/SUB] epitope, are highly conserved between influenza A viruses regardless of their subtype or host species of origin. We hypothesized that human influenza A viruses evade recognition of this epitope by impairing antigen processing and presentation by extra-epitopic amino acid substitutions. Activation of specific T cells was used as read out for antigen presentation. Here, we show that the M1[SUB]58-66[/SUB] epitope in the M1 protein derived from human influenza A virus was poorly recognized compared to the M1 protein derived from avian influenza A virus. Furthermore, we demonstrated that naturally occurring variation at extra-epitopic amino acid residues affect CD8[SUP]+[/SUP] T cell recognition of the M1[SUB]58-66[/SUB] epitope. These data indicate that human influenza A viruses can impair recognition by M1[SUB]58-66[/SUB]-specific CTLs, while retaining the conserved amino acid sequence of the epitope, which may represent a yet unknown immune evasion strategy for influenza A viruses. This difference in recognition may have implications for the viral replication kinetics in HLA-A*0201 individuals and spread of influenza A viruses in the human population. The findings may aid the rational design of universal influenza vaccines that aim at the induction of cross-reactive virus-specific CTL responses.
[h=4]IMPORTANCE:[/h] Influenza viruses are an important cause of acute respiratory tract infections. Natural influenza A virus infections elicit both humoral and cellular immunity. CD8[SUP]+[/SUP] cytotoxic T lymphocytes (CTLs) are directed predominantly against conserved internal proteins and confer cross-protection, even against influenza A viruses of various subtypes. In some CTL epitopes mutations occur that allow influenza A viruses to evade from recognition by CTLs. However, the immunodominant HLA-A*0201 restricted M1[SUB]58-66[/SUB] epitope does not tolerate mutations without loss of viral fitness. Here, we describe naturally occurring variations in amino acid residues outside the M1[SUB]58-66[/SUB] epitope that influence the recognition of the epitope. These results provide novel insights in the epidemiology of influenza A viruses and their pathogenicity and may aid rational design of vaccines that aim at the induction of CTL responses.
Copyright ? 2015, American Society for Microbiology. All Rights Reserved.
PMID: 26537686 [PubMed - as supplied by publisher]