The role of MHC class I allele Mamu-A07 during SIV(mac)239 infection

• Published in: Immunogenetics (New York) Vol. 63; no. 12; pp. 789 - 807
• Main Authors: Reed, Jason S, Sidney, John, Piaskowski, Shari M, Glidden, Chrystal E, León, Enrique J, Burwitz, Benjamin J, Kolar, Holly L, Eernisse, Christopher M, Furlott, Jessica R, Maness, Nicholas J, Walsh, Andrew D, Rudersdorf, Richard A, Bardet, Wilfried, McMurtrey, Curtis P, O'Connor, David H, Hildebrand, William H, Sette, Alessandro, Watkins, David I, Wilson, Nancy A
• Format: Journal Article
• Language: English
• Published: United States 01.12.2011
• Subjects: Alleles; Amino Acid Sequence; Animals; CD8-Positive T-Lymphocytes - immunology; Epitopes, T-Lymphocyte - analysis; Epitopes, T-Lymphocyte - chemistry; Epitopes, T-Lymphocyte - immunology; Genes, MHC Class I - genetics; Histocompatibility Antigens Class I - analysis; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - immunology; Interferon-gamma; Macaca mulatta; Protein Binding; RNA, Viral - blood; RNA, Viral - genetics; Sequence Analysis, Protein; Simian Acquired Immunodeficiency Syndrome - immunology; Simian Immunodeficiency Virus - classification; Simian Immunodeficiency Virus - immunology; Simian Immunodeficiency Virus - pathogenicity; T-Lymphocytes, Cytotoxic - immunology; Viral Load; Viral Vaccines
• ISSN: 1432-1211
• DOI: 10.1007/s00251-011-0541-9

Virus-specific CD8(+) T cells play an important role in controlling HIV/SIV replication. These T cells recognize intracellular pathogen-derived peptides displayed on the cell surface by individual MHC class I molecules. In the SIV-infected rhesus macaque model, five Mamu class I alleles have been thoroughly characterized with regard to peptide binding, and a sixth was shown to be uninvolved. In this study, we describe the peptide binding of Mamu-A1*007:01 (formerly Mamu-A*07), an allele present in roughly 5.08% of Indian-origin rhesus macaques (n = 63 of 1,240). We determined a preliminary binding motif by eluting and sequencing endogenously bound ligands. Subsequently, we used a positional scanning combinatorial library and panels of single amino acid substitution analogs to further characterize peptide binding of this allele and derive a quantitative motif. Using this motif, we selected and tested 200 peptides derived from SIV(mac)239 for their capacity to bind Mamu-A1*007:01; 33 were found to bind with an affinity of 500 nM or better. We then used PBMC from SIV-infected or vaccinated but uninfected, A1*007:01-positive rhesus macaques in IFN-γ Elispot assays to screen the peptides for T-cell reactivity. In all, 11 of the peptides elicited IFN-γ(+) T-cell responses. Six represent novel A1*007:01-restricted epitopes. Furthermore, both Sanger and ultradeep pyrosequencing demonstrated the accumulation of amino acid substitutions within four of these six regions, suggestive of selective pressure on the virus by antigen-specific CD8(+) T cells. Thus, it appears that Mamu-A1*007:01 presents SIV-derived peptides to antigen-specific CD8(+) T cells and is part of the immune response to SIV(mac)239.