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Journal of Virology, May 2004, p. 5216-5222, Vol. 78, No. 10
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.10.5216-5222.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

A Mutation in the HLA-B*2705-Restricted NP383-391 Epitope Affects the Human Influenza A Virus-Specific Cytotoxic T-Lymphocyte Response In Vitro

E. G. M. Berkhoff,1,2 A. C. M. Boon,1,2 N. J. Nieuwkoop,1,2 R. A. M. Fouchier,1,2 K. Sintnicolaas,3 A. D. M. E. Osterhaus,1,2 and G. F. Rimmelzwaan1,2*

Institute of Virology,1 WHO National Influenza Center, Erasmus Medical Center, Rotterdam,2 Laboratory for Histocompatibility and Immunogenetics, Sanquin Bloodbank, Dordrecht, The Netherlands3

Received 13 November 2003/ Accepted 16 January 2004

Viruses can exploit a variety of strategies to evade immune surveillance by cytotoxic T lymphocytes (CTL), including the acquisition of mutations in or adjacent to CTL epitopes. Recently, an amino acid substitution (R384G) in an HLA-B*2705-restricted CTL epitope in the influenza A virus nucleoprotein (nucleoprotein containing residues 383 to 391 [NP383-391]; SRYWAIRTR, where R is the residue that was mutated) was associated with escape from CTL-mediated immunity. The effect of this mutation on the in vitro influenza A virus-specific CTL response was studied. To this end, two influenza A viruses, one with and one without the NP383-391 epitope, were constructed by reverse genetics and designated influenza viruses A/NL/94-384R and A/NL/94-384G, respectively. The absence of the HLA-B*2705-restricted CTL epitope in influenza virus A/NL/94-384G was confirmed by using 51Cr release assays with a T-cell clone specific for the NP383-391 epitope. In addition, peripheral blood mononuclear cells (PBMC) stimulated with influenza virus A/NL/94-384G failed to recognize HLA-B*2705-positive target cells pulsed with the original NP383-391 peptide. The proportion of virus-specific CD8+ gamma interferon (IFN-{gamma})-positive T cells in in vitro-stimulated PBMC was determined by intracellular IFN-{gamma} staining after restimulation with virus-infected autologous B-lymphoblastoid cell lines and C1R cell lines expressing only HLA-B*2705. The proportion of virus-specific CD8+ T cells was lower in PBMC stimulated in vitro with influenza virus A/NL/94-384G obtained from several HLA-B*2705-positive donors than in PBMC stimulated with influenza virus A/NL/94-384R. This finding indicated that amino acid variations in CTL epitopes can affect the virus-specific CTL response and that the NP383-391 epitope is the most important HLA-B*2705-restricted epitope in the nucleoprotein of influenza A viruses.

* Corresponding author. Mailing address: Institute of Virology, Erasmus Medical Center, P. O. Box 1738, 3000 DR Rotterdam, The Netherlands. Phone: 31 104088243. Fax: 31 104089485. E-mail: g.rimmelzwaan{at}erasmusmc.nl.

Journal of Virology, May 2004, p. 5216-5222, Vol. 78, No. 10
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.10.5216-5222.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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