Definition of the Mamu A*01 Peptide Binding Specificity: Application to the Identification of Wild-Type and Optimized Ligands from Simian Immunodeficiency Virus Regulatory Proteins

Sidney, John; Dzuris, John L.; Newman, Mark J.; Johnson, R. Paul; Kaur, Amitinder; Walker, Christopher M.; Appella, Ettore; Mothé, Bianca R.; Watkins, David I.; Sette, Alessandro

doi:10.4049/jimmunol.165.11.6387

Cited by 48 publications

(60 citation statements)

References 52 publications

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“…Mamu-A*01, which represents the best-studied rhesus Mhc allele, 34,35 was encoded in haplotype 4. Six monkeys carrying this and group 1 haplotypes were derived from three breeding groups.…”

Section: Haplotypes Associated With Slow Disease Progressionmentioning

confidence: 99%

Mhc class I haplotypes associated with survival time in simian immunodeficiency virus (SIV)-infected rhesus macaques

Sauermann

Siddiqui

et al. 2007

Genes Immun

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In both human immunodeficiency virus-infected humans and simian immunodeficiency virus (SIV)-infected macaques, genes encoded in the major histocompatibility complex (MHC) class I region are important determinants of disease progression. However, compared to the human human lymphocyte antigen complex, the macaque MHC region encodes many more class I genes. Macaques with the same immunodominant class I genes express additional Mhc genes with the potential to influence the disease course. We therefore assessed the association between of the Mhc class I haplotypes, rather than single gene variants, and survival time in SIV-infected rhesus macaques (Macaca mulatta). DNA sequence analysis and Mhc genotyping of 245 pedigreed monkeys identified 17 Mhc class I haplotypes that constitute 10 major genotypes. Among 81 vaccination-naive, SIV-infected macaques, 71 monkeys carried at least one Mhc class I haplotype encoding only MHC antigens that were incapable of inducing an effective anti-SIV cytotoxic T lymphocytes response. Study of these macaques enabled us to relate individual Mhc class I haplotypes to slow, medium and rapid disease progression. In a post hoc analysis, classification according to disease progression was found to explain at least 48% of the observed variation of survival time.

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“…Mamu-A*01, which represents the best-studied rhesus Mhc allele, 34,35 was encoded in haplotype 4. Six monkeys carrying this and group 1 haplotypes were derived from three breeding groups.…”

Section: Haplotypes Associated With Slow Disease Progressionmentioning

confidence: 99%

Mhc class I haplotypes associated with survival time in simian immunodeficiency virus (SIV)-infected rhesus macaques

Sauermann

Siddiqui

et al. 2007

Genes Immun

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“…Previous research on the Mamu-A*02 molecule described two CD8 ϩ T cell epitopes and proposed a tentative peptide-binding motif defining primary anchor residues that was derived from analysis of eluted natural ligands and in vitro binding assays (26,50). However, several studies indicate that both primary and secondary anchors must be taken into account together with the use of in vitro peptide/MHC-binding assays to accurately identify potential T cell epitopes (52)(53)(54)(55). Once peptides binding with reasonable affinity are identified, they can be tested for CD8 ϩ T cell recognition from infected animals.…”

Section: Specific Cd8mentioning

confidence: 99%

“…ARB was derived for each residue considered individually when there were five or more occurrences of that residue in the specified position in the peptide library. When there were fewer than five occurrences (e.g., M, C, or W), ARB calculations include data obtained from a group of chemically similar amino acids as previously described (47,52,54,55,(63)(64)(65)(66). Amino acids with ARB values Ն0.1 are considered preferred residues, 0.01-0.1 are defined as tolerated, and Ͻ0.01 indicate nontolerated.…”

Section: Computational Peptide Binding and Bioinformatic Analysismentioning

confidence: 99%

“…For detailed analysis of the peptide binding data, binding values were standardized by calculation of a geometric mean, or average relative binding (ARB) value, for all peptides of a particular chemical specificity (47,52,54,55,(63)(64)(65)(66). For peptides of identical size, binding capacity was further analyzed by determining the ARB values for all peptides that contain a particular amino acid residue in a specific position.…”

Section: Computational Peptide Binding and Bioinformatic Analysismentioning

confidence: 99%

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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

Sidney

Wojewoda

et al. 2004

The Journal of Immunology

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113

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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 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-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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“…At all positions, we designed a set of substitutions to provide at least one example of a conservative, semiconservative, and nonconservative substitution (Table III). In the present analyses, as in previous studies of HLA class I molecules (26,46,47), preferred residues at each position were defined as those whose average relative binding capacity (ARB) was Ն0.1, when compared with the binding capacity of the optimal residue at the same position. We defined residues with an ARB between 0.01 and 0.1 as tolerated.…”

Section: Determination Of the Primary Anchor Specificity For Mamu-b*0mentioning

confidence: 99%

The High Frequency Indian Rhesus Macaque MHC Class I Molecule, Mamu-B*01, Does Not Appear to Be Involved in CD8+ T Lymphocyte Responses to SIVmac239

Loffredo

Sidney

Piaskowski

et al. 2005

The Journal of Immunology

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Although the SIV-infected Indian rhesus macaque (Macaca mulatta) is the animal model most widely used for studying HIV infection, our current understanding of the functional macaque MHC class I molecules is limited. To date, SIV-derived CD8+ T lymphocyte epitopes from only three high frequency macaque MHC class I molecules have been extensively characterized. In this study, we defined the peptide-binding properties of the high frequency Indian rhesus macaque class I molecule, Mamu-B*01 (∼26%). We first identified a preliminary binding motif by eluting and sequencing endogenously bound Mamu-B*01 ligands. We further characterized the peptide-binding characteristics using panels of single amino acid substitution analogs. Using this detailed motif, 507 peptides derived from SIVmac239 were identified and tested for their Mamu-B*01 binding capacity. Surprisingly, only 11 (2.2%) of these motif-containing peptides bound with IC50 values ≤500 nM. We assessed the immunogenicity of these peptides using freshly isolated PBMC from ten Mamu-B*01+ SIV-infected rhesus macaques in IFN-γ ELISPOT and IFN-γ/TNF-α intracellular cytokine staining assays. Lymphocytes from these SIV-infected macaques responded to none of these peptides. Furthermore, there was no sequence variation indicative of escape in the regions of the virus that encoded these peptides. Additionally, we could not confirm previous reports of SIV-derived Mamu-B*01-restricted epitopes in the Env and Gag proteins. Our results suggest that the high frequency MHC class I molecule, Mamu-B*01, is not involved in SIV-specific CD8+ T lymphocyte responses.

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Definition of the Mamu A*01 Peptide Binding Specificity: Application to the Identification of Wild-Type and Optimized Ligands from Simian Immunodeficiency Virus Regulatory Proteins

Cited by 48 publications

References 52 publications

Mhc class I haplotypes associated with survival time in simian immunodeficiency virus (SIV)-infected rhesus macaques

Mhc class I haplotypes associated with survival time in simian immunodeficiency virus (SIV)-infected rhesus macaques

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

The High Frequency Indian Rhesus Macaque MHC Class I Molecule, Mamu-B*01, Does Not Appear to Be Involved in CD8+ T Lymphocyte Responses to SIVmac239

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