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Journal of Virology, September 2009, p. 9206-9214, Vol. 83, No. 18
0022-538X/09/$08.00+0     doi:10.1128/JVI.00932-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

T-Cell Tolerance for Variability in an HLA Class I-Presented Influenza A Virus Epitope{triangledown}

Angela Wahl,1 William McCoy,2 Fredda Schafer,1 Wilfried Bardet,1 Rico Buchli,3 Daved H. Fremont,2,4 and William H. Hildebrand1*

Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, 975 Northeast 10th Street, Oklahoma City, Oklahoma, 73104,1 Department of Pathology and Immunology,2 Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110,4 Pure Protein L.L.C., 800 Research Parkway, Suite 340, Oklahoma City, Oklahoma 731043

Received 11 May 2009/ Accepted 21 June 2009

To escape immune recognition, viruses acquire amino acid substitutions in class I human leukocyte antigen (HLA)-presented cytotoxic T-lymphocyte (CTL) epitopes. Such viral escape mutations may (i) prevent peptide processing, (ii) diminish class I HLA binding, or (iii) alter T-cell recognition. Because residues 418 to 426 of the hypervariable influenza A virus nucleoprotein (NP418-426) epitope are consistently bound by class I HLA and presented to CTL, we assessed the impact that intraepitope sequence variability has upon T-cell recognition. CTL elicited by intranasal influenza virus infection were tested for their cross-recognition of 20 natural NP418-426 epitope variants. Six of the variant epitopes, of both H1N1 and H3N2 origin, were cross-recognized by CTL while the remaining NP418-426 epitope variants escaped targeting. A pattern emerged whereby variability at position 5 (P5) within the epitope reduced T-cell recognition, changes at P4 or P6 enabled CTL escape, and a mutation at P8 enhanced T-cell recognition. These data demonstrate that substitutions at P4 and/or P6 facilitate influenza virus escape from T-cell recognition and provide a model for the number, nature, and location of viral mutations that influence T-cell cross-recognition.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, 975 NE 10th Street, Oklahoma City, OK 73104. Phone: (405) 271-1203. Fax: (405) 271-3117. E-mail: William-Hildebrand{at}ouhsc.edu

{triangledown} Published ahead of print on 24 June 2009.

Journal of Virology, September 2009, p. 9206-9214, Vol. 83, No. 18
0022-538X/09/$08.00+0     doi:10.1128/JVI.00932-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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