Functional constraints of influenza A virus epitopes limit escape from cytotoxic T lymphocytes

E. G.M. Berkhoff, E. De Wit, M. M. Geelhoed-Mieras, A. C.M. Boon, J. Symons, R. A.M. Fouchier, A. D.M.E. Osterhaus, G. F. Rimmelzwaan

Research output: Contribution to journalArticle

76 Scopus citations


Viruses can exploit a variety of strategies to evade immune surveillance by cytotoxic T lymphocytes (CTL), including the acquisition of mutations in CTL epitopes. Also for influenza A viruses a number of amino acid substitutions in the nucleoprotein (NP) have been associated with escape from CTL. However, other previously identified influenza A virus CTL epitopes are highly conserved, including the immunodominant HLA-A*0201-restricted epitope from the matrix protein, M158-66. We hypothesized that functional constraints were responsible for the conserved nature of influenza A virus CTL epitopes, limiting escape from CTL. To assess the impact of amino acid substitutions in conserved epitopes on viral fitness and recognition by specific CTL, we performed a mutational analysis of CTL epitopes. Both alanine replacements and more conservative substitutions were introduced at various positions of different influenza A virus CTL epitopes. Alanine replacements for each of the nine amino acids of the M158-66 epitope were tolerated to various extents, except for the anchor residue at the second position. Substitution of anchor residues in other influenza A virus CTL epitopes also affected viral fitness. Viable mutant viruses were used in CTL recognition experiments. The results are discussed in the light of the possibility of influenza viruses to escape from specific CTL. It was speculated that functional constraints limit variation in certain epitopes, especially at anchor residues, explaining the conserved nature of these epitopes.

Original languageEnglish
Pages (from-to)11239-11246
Number of pages8
JournalJournal of virology
Issue number17
StatePublished - Sep 1 2005
Externally publishedYes

Fingerprint Dive into the research topics of 'Functional constraints of influenza A virus epitopes limit escape from cytotoxic T lymphocytes'. Together they form a unique fingerprint.

  • Cite this

    Berkhoff, E. G. M., De Wit, E., Geelhoed-Mieras, M. M., Boon, A. C. M., Symons, J., Fouchier, R. A. M., Osterhaus, A. D. M. E., & Rimmelzwaan, G. F. (2005). Functional constraints of influenza A virus epitopes limit escape from cytotoxic T lymphocytes. Journal of virology, 79(17), 11239-11246.