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A Single Amino Acid Difference within the -2 Domain of Two Naturally Occurring Equine MHC Class I Molecules Alters the Recognition of Gag and Rev Epitopes by Equine Infectious Anemia Virus-Specific CTL¹

Robert H. Mealey^2,*, Jae-Hyung Lee, Steven R. Leib^*, Matt H. Littke^* and Travis C. McGuire^*

^* Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164; and Bioinformatics and Computational Biology Program, Iowa State University, Ames, IA 50011

Although CTL are critical for control of lentiviruses, including equine infectious anemia virus, relatively little is known regarding the MHC class I molecules that present important epitopes to equine infectious anemia virus-specific CTL. The equine class I molecule 7-6 is associated with the equine leukocyte Ag (ELA)-A1 haplotype and presents the Env-RW12 and Gag-GW12 CTL epitopes. Some ELA-A1 target cells present both epitopes, whereas others are not recognized by Gag-GW12-specific CTL, suggesting that the ELA-A1 haplotype comprises functionally distinct alleles. The Rev-QW11 CTL epitope is also ELA-A1-restricted, but the molecule that presents Rev-QW11 is unknown. To determine whether functionally distinct class I molecules present ELA-A1-restricted CTL epitopes, we sequenced and expressed MHC class I genes from three ELA-A1 horses. Two horses had the 7-6 allele, which when expressed, presented Env-RW12, Gag-GW12, and Rev-QW11 to CTL. The other horse had a distinct allele, designated 141, encoding a molecule that differed from 7-6 by a single amino acid within the -2 domain. This substitution did not affect recognition of Env-RW12, but resulted in more efficient recognition of Rev-QW11. Significantly, CTL recognition of Gag-GW12 was abrogated, despite Gag-GW12 binding to 141. Molecular modeling suggested that conformational changes in the 141/Gag-GW12 complex led to a loss of TCR recognition. These results confirmed that the ELA-A1 haplotype is comprised of functionally distinct alleles, and demonstrated for the first time that naturally occurring MHC class I molecules that vary by only a single amino acid can result in significantly different patterns of epitope recognition by lentivirus-specific CTL.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by U.S. Public Health Service, National Institutes of Health Grants AI058787 (to R.H.M. and T.C.M.), AI067125 (to R.H.M. and T.C.M.), AI060395 (to T.C.M. and R.H.M.), CA97936 (to J.L.), U.S. Department of Agriculture National Research Initiative Grant 2002-35204-12699 (to J.L.), and the Center for Integrated Animal Genomics at Iowa State University (to J.L.).

² Address correspondence and reprint requests to Dr. Robert H. Mealey, Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA 99164-7040. E-mail address: rhm{at}vetmed.wsu.edu

³ Abbreviations used in this paper: EIAV, equine infectious anemia virus; MHC I, MHC class I; β₂m, β₂-microglobulin; ELA, equine leukocyte Ag; EK, equine kidney.