Definition of the Mamu A01 Peptide Binding Specificity: Application to the Identification of Wild-Type and Optimized Ligands from Simian Immunodeficiency Virus Regulatory Proteins

• Published in: The Journal of immunology (1950) Vol. 165; no. 11; pp. 6387 - 6399
• Main Authors: Sidney, John, Dzuris, John L, Newman, Mark J, Johnson, R. Paul, Amitinder, Kaur, Walker, Christopher M, Appella, Ettore, Mothe, Bianca, Watkins, David I, Sette, Alessandro
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01.12.2000
• Subjects: Algorithms; Amino Acid Substitution; Amino Acids - metabolism; Animals; Binding Sites - immunology; Epitopes, T-Lymphocyte - metabolism; gag protein; histocompatibility antigen Mamu; Histocompatibility Antigens Class I - metabolism; Immediate-Early Proteins - chemical synthesis; Immediate-Early Proteins - metabolism; Ligands; Macaca mulatta; Oligopeptides - chemical synthesis; Oligopeptides - metabolism; Peptide Fragments - chemical synthesis; Peptide Fragments - metabolism; Peptide Mapping; Protein Binding - immunology; Protein Engineering; Simian immunodeficiency virus; Simian Immunodeficiency Virus - immunology; Simian Immunodeficiency Virus - metabolism; Viral Regulatory and Accessory Proteins - chemical synthesis; Viral Regulatory and Accessory Proteins - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.165.11.6387

Single amino acid substitution analogs of the known Mamu A*01 binding peptide gag 181-190 and libraries of naturally occurring sequences of viral or bacterial origin were used to rigorously define the peptide binding motif associated with Mamu A*01 molecules. The presence of S or T in position 2, P in position 3, and hydrophobic or aromatic residues at the C terminus is associated with optimal binding capacity. At each of these positions, additional residues are also tolerated but associated with significant decreases in binding capacity. The presence of at least two preferred and one tolerated residues at the three anchor positions is necessary for good Mamu A*01 binding; optimal ligand size is 8-9 residues. This detailed motif has been used to map potential epitopes from SIVmac239 regulatory proteins and to engineer peptides with increased binding capacity. A total of 13 wild type and 17 analog candidate epitopes were identified. Furthermore, our analysis reveals a significantly lower than expected frequency of epitopes in early regulatory proteins, suggesting a possible evolutionary- and/or immunoselection directed against variants of viral products that contain CTL epitopes.