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

John T. Loffredo, John Sidney, Christina Wojewoda, Elizabeth Dodds, Matthew R. Reynolds, Gnankang Napoé, Bianca R. Mothé, David H. O'Connor, Nancy A. Wilson, David Watkins, Alessandro Sette

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

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 aleles, Mamu-A*01 and Mamu-B*17. As a result, these two molecules account for virtually all known MHC class I-restricted SIV-dserived CD8+ T cell epiftopes. 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 SIVmac239 peptides that fit the Mamu-A*02 peptide-binding motif, 75 peptides bound Mamu-A*02 with IC50 values of ≤500 nM. We assessed the antigenicity of these 75 peptides using an IFN-γ 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-γ secretion by SIV-speciflc 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.

Original languageEnglish
Pages (from-to)5064-5076
Number of pages13
JournalJournal of Immunology
Volume173
Issue number8
StatePublished - Oct 15 2004
Externally publishedYes

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Simian Immunodeficiency Virus
T-Lymphocyte Epitopes
Macaca
Peptides
T-Lymphocytes
Epitopes
Macaca mulatta
Infection
HIV
Enzyme-Linked Immunospot Assay
Amino Acid Substitution
Mamu-A 02 antigen
Gene Frequency
Inhibitory Concentration 50
Vaccines
Alleles
Amino Acids
Research

ASJC Scopus subject areas

  • Immunology

Cite this

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. / Loffredo, John T.; Sidney, John; Wojewoda, Christina; Dodds, Elizabeth; Reynolds, Matthew R.; Napoé, Gnankang; Mothé, Bianca R.; O'Connor, David H.; Wilson, Nancy A.; Watkins, David; Sette, Alessandro.

In: Journal of Immunology, Vol. 173, No. 8, 15.10.2004, p. 5064-5076.

Research output: Contribution to journalArticle

Loffredo, JT, Sidney, J, Wojewoda, C, Dodds, E, Reynolds, MR, Napoé, G, Mothé, BR, O'Connor, DH, Wilson, NA, Watkins, D & Sette, A 2004, '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', Journal of Immunology, vol. 173, no. 8, pp. 5064-5076.
Loffredo, John T. ; Sidney, John ; Wojewoda, Christina ; Dodds, Elizabeth ; Reynolds, Matthew R. ; Napoé, Gnankang ; Mothé, Bianca R. ; O'Connor, David H. ; Wilson, Nancy A. ; Watkins, David ; Sette, Alessandro. / 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. In: Journal of Immunology. 2004 ; Vol. 173, No. 8. pp. 5064-5076.
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abstract = "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 aleles, Mamu-A*01 and Mamu-B*17. As a result, these two molecules account for virtually all known MHC class I-restricted SIV-dserived CD8+ T cell epiftopes. 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 SIVmac239 peptides that fit the Mamu-A*02 peptide-binding motif, 75 peptides bound Mamu-A*02 with IC50 values of ≤500 nM. We assessed the antigenicity of these 75 peptides using an IFN-γ 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-γ secretion by SIV-speciflc 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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AU - Loffredo, John T.

AU - Sidney, John

AU - Wojewoda, Christina

AU - Dodds, Elizabeth

AU - Reynolds, Matthew R.

AU - Napoé, Gnankang

AU - Mothé, Bianca R.

AU - O'Connor, David H.

AU - Wilson, Nancy A.

AU - Watkins, David

AU - Sette, Alessandro

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