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Journal of Virology, September 2005, p. 11239-11246, Vol. 79, No. 17
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.17.11239-11246.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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, and G. F. Rimmelzwaan*

Department of Virology and WHO National Influenza Center, Erasmus Medical Center, Rotterdam, The Netherlands

Received 16 March 2005/ Accepted 9 June 2005

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.

* Corresponding author. Mailing address: Erasmus Medical Center, Department of Virology, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. Phone: 31-10-4088243. Fax: 31-10-4089485. E-mail: g.rimmelzwaan{at}erasmusmc.nl.

Journal of Virology, September 2005, p. 11239-11246, Vol. 79, No. 17
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.17.11239-11246.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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