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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-2Db but Not H-2Kb

Maryann T. Puglielli,1 Allan J. Zajac,1,dagger Robbert G. van der Most,1 John L. Dzuris,2 Alessandro Sette,2 John D. Altman,1 and Rafi Ahmed1,*

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-2Db-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 Db-restricted GP33-43 epitope and a second epitope (GP34-42) presented by the Kb molecule. We determined that the V-to-A CTL escape mutant failed to induce a Db GP33-43-specific CTL response and that Db-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 Kb-restricted response was much less affected. We found that the V-to-A substitution severely impaired peptide binding to Db but not to Kb 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 Db binding explains why the variant virus escapes the Db GP33-43-specific response but still elicits the Kb-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.

* 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.

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

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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