title: The role of MHC class I allele Mamu-A*07 during SIV(mac)239 infection.
abstract: 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.
authors: Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, USA.
authors: Jason S
authors: JS
authors: Reed
authors: John
authors: J
authors: Sidney
authors: Shari M
authors: SM
authors: Piaskowski
authors: Chrystal E
authors: CE
authors: Glidden
authors: Enrique J
authors: EJ
authors: León
authors: Benjamin J
authors: BJ
authors: Burwitz
authors: Holly L
authors: HL
authors: Kolar
authors: Christopher M
authors: CM
authors: Eernisse
authors: Jessica R
authors: JR
authors: Furlott
authors: Nicholas J
authors: NJ
authors: Maness
authors: Andrew D
authors: AD
authors: Walsh
authors: Richard A
authors: RA
authors: Rudersdorf
authors: Wilfried
authors: W
authors: Bardet
authors: Curtis P
authors: CP
authors: McMurtrey
authors: David H
authors: DH
authors: O'Connor
authors: William H
authors: WH
authors: Hildebrand
authors: Alessandro
authors: A
authors: Sette
authors: David I
authors: DI
authors: Watkins
authors: Nancy A
authors: NA
authors: Wilson
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000032:analysis / Q000737:chemistry / Q000276:immunology; D005805:Genes, MHC Class I / Q000235:genetics*; D015395:Histocompatibility Antigens Class I / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D007371:Interferon-gamma; D008253:Macaca mulatta; D011485:Protein Binding; D012367:RNA, Viral / Q000097:blood / Q000235:genetics; D020539:Sequence Analysis, Protein; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology*; D015302:Simian Immunodeficiency Virus / Q000145:classification / Q000276:immunology* / Q000472:pathogenicity; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019562:Viral Load; D014765:Viral Vaccines
chemical_list: D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D012367:RNA, Viral; D014765:Viral Vaccines; D007371:Interferon-gamma