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Journal of Virology, June 2001, p. 5099-5107, Vol. 75, No. 11
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.11.5099-5107.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

In Vivo Selection of a Lymphocytic Choriomeningitis Virus Variant That Affects Recognition of the GP33-43 Epitope by H-2D^b but Not H-2K^b

Maryann T. Puglielli,¹ Allan J. Zajac,^1, Robbert G. van der Most,¹ John L. Dzuris,² Alessandro Sette,² John D. Altman,¹ and Rafi Ahmed^1,*

Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322,¹ and Epimmune, Inc., San Diego, California 92121, and Department of Analytical Sciences and Immunological Diseases, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877²

Received 28 October 1999/Accepted 6 March 2001

CD8 T cells drive the protective immune response to lymphocytic choriomeningitis virus (LCMV) infection and are thus a determining force in the selection of viral variants. To examine how escape mutations affect the presentation and recognition of overlapping T-cell epitopes, we isolated an LCMV variant that is not recognized by T-cell receptor (TCR)-transgenic H-2D^b-restricted LCMV GP33-41-specific cytotoxic T lymphocytes (CTL). The variant virus carried a single-amino-acid substitution (valine to alanine) at position 35 of the viral glycoprotein. This region of the LCMV glycoprotein encodes both the D^b-restricted GP33-43 epitope and a second epitope (GP34-42) presented by the K^b molecule. We determined that the V-to-A CTL escape mutant failed to induce a D^b GP33-43-specific CTL response and that D^b-restricted GP33-43-specific CTL induced by the wild-type LCMV strain were unable to kill target cells infected with the variant LCMV strain. In contrast, the K^b-restricted response was much less affected. We found that the V-to-A substitution severely impaired peptide binding to D^b but not to K^b molecules. Strikingly, the V-to-A mutation did not change any of the anchor residues, and the dramatic effect on binding was therefore unexpected. The strong decrease in D^b binding explains why the variant virus escapes the D^b GP33-43-specific response but still elicits the K^b-restricted response. These findings also illustrate that mutations within regions encoding overlapping T-cell epitopes can differentially affect the presentation and recognition of individual epitopes.

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^* Corresponding author. Mailing address: Emory University School of Medicine, 1510 Clifton Rd., Atlanta, GA 30322. Phone: (404) 727-3571. Fax: (404) 727-3722. E-mail: ra{at}microbio.emory.edu.

Present address: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294-2170.

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Journal of Virology, June 2001, p. 5099-5107, Vol. 75, No. 11
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.11.5099-5107.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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