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J. Biol. Chem., Vol. 281, Issue 29, 20205-20212, July 21, 2006

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Structural Basis for Degenerate Recognition of Natural HIV Peptide Variants by Cytotoxic Lymphocytes^*

Erik Martinez-Hackert¹², Nadia Anikeeva¹³, Spyros A. Kalams^¶, Bruce D. Walker^||**, Wayne A. Hendrickson, and Yuri Sykulev⁴

From the Department of Microbiology and Immunology and Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, the Department of Biochemistry and Molecular Biophysics and Howard Hughes Medical Institute, Columbia University, New York, New York 10032, ^¶Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee 37232, and the ^||AIDS Research Center, Massachusetts General Hospital and ^**Howard Hughes Medical Institute, Boston, Massachusetts 02114

It is well established that even small changes in amino acid side chains of antigenic peptide bound to major histocompatibility complex (MHC) protein may completely abrogate recognition of the peptide-MHC (pMHC) complex by the T cell receptor (TCR). Often, however, several nonconservative substitutions in the peptide antigen are accommodated and do not impair its recognition by TCR. For example, a preponderance of natural sequence variants of the human immunodeficiency virus p17 Gag-derived peptide SLYNTVATL (SL9) are recognized by cytotoxic T lymphocytes, which implies that interactions with SL9 variants are degenerate both with respect to the class I MHC molecule and with respect to TCR. Here we study the molecular basis for this degenerate recognition of SL9 variants. We show that several SL9 variants bind comparably well to soluble HLA-A2 and to a particular soluble TCR and that these variants are active in the cognate cytotoxicity assay. Natural SL9 variation is restricted by its context in the HIV p17 matrix protein. High resolution crystal structures of seven selected SL9 variants bound to HLA-A2 all have remarkably similar peptide conformations and side-chain dispositions outside sites of substitution. This preservation of the peptide conformation despite epitope variations suggests a mechanism for the observed degeneracy in pMHC recognition by TCR and may contribute to the persistence of SL9-mediated immune responses in chronically infected individuals.

Received for publication, February 28, 2006 , and in revised form, April 28, 2006.

^* This work was supported in part by National Institutes of Health Research Grants AI43254 and AI58755, The W. W. Smith Charitable Trust Award (to Y. S.), and National Institutes of Health Research Grant AI39966 (to S. K.). 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.

The atomic coordinates and structure factors (code 1T21, 1S8D, 1T1W, 1T1X, 1T1Y, 1T20, 1T1Z, 1T22) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1S.

¹ Both authors contributed equally to this work.

² Fellow of the Leukemia and Lymphoma Society of America and the Jane Elissa/Charlotte Meyers Endowment Fund.

³ Supported by National Research Service Award 5-T32-AI07523 Training Program for AIDS Research.

⁴ To whom correspondence should be addressed: Dept. of Microbiology and Immunology, Kimmel Cancer Center, BLSB 650, Thomas Jefferson University, Philadelphia, PA 19107. Tel.: 215-503-4530; Fax: 215-923-0249; E-mail: ysykulev{at}lac.jci.tju.edu.

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