Identification of seventeen new simian immunodeficiency virus-derived CD8+ T cell epitopes restricted by the high frequency molecule, Mamu-A*02, and potential escape from CTL recognition

被引:78
作者
Loffredo, JT
Sidney, J
Wojewoda, C
Dodds, E
Reynolds, MR
Napoé, G
Mothé, BR
O'Connor, DH
Wilson, NA
Watkins, DI
Sette, A
机构
[1] La Jolla Inst Allergy & Immunol, San Diego, CA 92109 USA
[2] Univ Wisconsin, Natl Primate Res Ctr, WPRC, Madison, WI 53715 USA
[3] Univ Wisconsin, Sch Med, Dept Pathol & Lab Med, Madison, WI 53706 USA
[4] Calif State Univ, Dept Biol Sci, San Marcos, CA 92096 USA
关键词
D O I
10.4049/jimmunol.173.8.5064
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
MHC class I-restricted CD8(+) T cells play an important role in controlling HIV and SIV replication. In SIV-infected Indian rhesus macaques (Macaca mulatta), comprehensive CD8(+) T cell epitope identification has only been undertaken for two alleles, Mamu-A*01 and Mamu-B*17. As a result, these two molecules account for virtually all known MHC class I-restricted SIV-derived CD8(+) T cell epitopes. SIV pathogenesis research and vaccine testing have intensified the demand for epitopes restricted by additional MHC class I alleles due to the shortage of Mamu-A*01(+) animals. Mamu-A(*)02 is a high frequency allele present in over 20% of macaques. In this study, we characterized the peptide binding of Mamu-A*02 using a panel of single amino acid substitution analogues and a library of 497 unrelated peptides. Of 230 SIV(mac)239 peptides that fit the Mamu-A*02 peptide-binding motif, 75 peptides bound Mamu-A*02 with IC50 values of less than or equal to500 nM. We assessed the antigenicity of these 75 peptides using an IFN-gamma ELISPOT assay with freshly isolated PBMC from eight Mamu-A*02(+) SIV-infected macaques and identified 17 new epitopes for Mamu-A*02. The synthesis of five Mamu-A*02 tetramers demonstrated the discrepancy between tetramer binding and IFN-gamma secretion by SIV-specific CD8(+) T cells during chronic SIV infection. Bulk sequencing determined that 2 of the 17 epitopes accumulated amino acid replacements in SIV-infected macaques by the chronic phase of infection, suggestive of CD8(+) T cell escape in vivo. This work enhances the use of the SIV-infected macaque model for HIV and increases our understanding of the breadth of CD8(+) T cell responses in SIV infection.
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页码:5064 / 5076
页数:13
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