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During most eukaryotic translation processes, the small 40S ribosome subunit scans an mRNA from its 5' end until it encounters the first start AUG codon. The large 60S ribosomal subunit then joins the smaller one to initiate protein synthesis. The location of the translation initiation is largely determined by the nucleotides near the start codon as there may be multiple translation initiation sites present on the mRNA.  Marilyn Kozak discovered that the sequence RCCAUGG (where R stands for...
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Use of Interferon-γ Enzyme-linked Immunospot Assay to Characterize Novel T-cell Epitopes of Human Papillomavirus
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Influenza virus CTL epitopes, remarkably conserved and remarkably variable.

Guus F Rimmelzwaan1, Joost H C M Kreijtz, Rogier Bodewes

  • 1Department of Virology, Erasmus Medical Center, Rotterdam, The Netherlands. g.rimmelzwaan@erasmusmc.nl

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Summary

Cytotoxic T lymphocytes (CTL) are crucial for controlling influenza virus infections, especially when antibodies fail. While many CTL epitopes are conserved, some variations in influenza A/H3N2 viruses impact T cell recognition and immune response.

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Area of Science:

  • Immunology
  • Virology
  • Molecular Biology

Background:

  • Virus-specific cytotoxic T lymphocytes (CTL) are vital for controlling viral infections, including influenza.
  • Antibodies can be insufficient against drifted or pandemic influenza strains, highlighting the importance of CTL for protective immunity.
  • Pre-existing CTL targeting conserved internal viral proteins may offer cross-protective immunity during influenza outbreaks.

Purpose of the Study:

  • To investigate the conservation and variation of T cell epitopes in influenza viruses.
  • To understand how amino acid substitutions in CTL epitopes affect viral recognition and immune responses.
  • To explore the functional constraints and evolutionary dynamics of influenza virus CTL epitopes.

Main Methods:

  • Analysis of known human influenza virus CTL epitopes.
  • Examination of amino acid substitutions in epitopes, including anchor and T cell receptor contact residues.
  • Mutational analysis of specific epitopes, such as M1(58-66), to assess functional constraints.

Main Results:

  • Most human influenza virus CTL epitopes are conserved, providing potential cross-protection.
  • Variations in CTL epitopes have been observed in influenza A/H3N2 viruses, affecting CTL recognition and in vitro responses.
  • Specific substitutions, like R384G in NP(383-391), can be detrimental to viral fitness unless compensated by co-mutations.
  • Highly immunodominant epitopes, such as M1(58-66) restricted by HLA-A*0201, are highly conserved due to functional constraints, even in other subtypes like H5N1.

Conclusions:

  • CTL responses are critical for influenza control, particularly when humoral immunity is inadequate.
  • While many CTL epitopes are conserved, variations in influenza A/H3N2 viruses can impact immune evasion.
  • Functional constraints play a significant role in maintaining the conservation of key immunodominant CTL epitopes, ensuring their continued effectiveness against influenza viruses.