TY - JOUR
T1 - The role of MHC class I allele Mamu-A *07 during SIV mac239 infection
AU - Reed, Jason S.
AU - Sidney, John
AU - Piaskowski, Shari M.
AU - Glidden, Chrystal E.
AU - León, Enrique J.
AU - Burwitz, Benjamin J.
AU - Kolar, Holly L.
AU - Eernisse, Christopher M.
AU - Furlott, Jessica R.
AU - Maness, Nicholas J.
AU - Walsh, Andrew D.
AU - Rudersdorf, Richard A.
AU - Bardet, Wilfried
AU - McMurtrey, Curtis P.
AU - O'Connor, David H.
AU - Hildebrand, William H.
AU - Sette, Alessandro
AU - Watkins, David I.
AU - Wilson, Nancy A.
N1 - Funding Information:
Acknowledgments We thank Gretta Borchardt and Chrystal Glidden for PCR–SSP typing and Lyle Wallace for the cDNA library work and resulting database. We also appreciate Alex Bean for assistance with immunological assays. The following reagents were obtained through the National Institutes of Health AIDS Research and Reference Reagent Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health: IL-2, human (item no. 136) from Hoffman-La Roche and SIVmac239 Vpr Peptides (6449) and SIVmac239 Pol Peptides (6443)from DAIDS, NIAID. This research was supported in part by grant R24 RR015371 (D.I.W.) from the National Institutes of Health, and in part by NIH grant number P51 RR000167 to the Wisconsin National Primate Research Center, University of Wisconsin– Madison. We would also like to thank Carrie Moore, Amiyah Steen, and Sandy Ngo for performing MHC purification and peptide binding studies.
PY - 2011/12
Y1 - 2011/12
N2 - 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 mac239 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 mac239.
AB - 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 mac239 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 mac239.
KW - Epitope
KW - Escape
KW - MHC
KW - Macaque
KW - SIV
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U2 - 10.1007/s00251-011-0541-9
DO - 10.1007/s00251-011-0541-9
M3 - Article
C2 - 21732180
AN - SCOPUS:82755198004
SN - 0093-7711
VL - 63
SP - 789
EP - 807
JO - Immunogenetics
JF - Immunogenetics
IS - 12
ER -