The role of MHC class I allele Mamu-A*07 during SIVmac239 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 1240). 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 SIVmac239 for their capacity to bind Mamu-A1*007:01, 33 were found to bind with an affinity of 500nM 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, eleven of the peptides elicited IFN-γ+ T cell responses. Six represent novel A1*007:01-restricted epitopes. Furthermore, both Sanger and ultra-deep 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 SIVmac239.

The common equine class I molecule Eqca-1*00101 (ELA-A3.1) is characterized by narrow peptide binding and T cell epitope repertoires

“…PSCL matrices have proven to be an efficient means for identifying MHC class I binding peptides (Udaka et al 1995; Stryhn et al 1996; Udaka et al 2000; Lauemoller et al 2001; Peters et al 2006; Sidney et al 2007; Sidney et al 2008a; Loffredo et al 2009; Reed et al 2011; Southwood et al 2011). Accordingly, we scored all 9-mer peptides in the EHV-1 proteome (strain Ab4) using the PSCL-based matrix shown in Table 2, where the score for each peptide is the product of the values for each peptide residue-position pair.…”

Characterization of the peptide binding specificity of the HLA class I alleles B*38:01 and B*39:06

“…The IC50 nM value for each substituted peptide was standardized as a ratio to the IC50 nM of the wild type peptide (Table 1). Finally, and as done previously with similar data (Reed et al 2011; Sidney et al 2008a), we calculated for each position a ratio of the (geometric) average relative binding (ARB) of all substitutions at a given position to the affinity of the wild type peptide. This ratio, denominated the specificity factor (SF), identifies positions where the majority of residues are associated with significant decreases in binding capacity; that is, positions with the highest specificity will have the highest SF value.…”

Influence of Naturally Occurring Simian Foamy Viruses (SFVs) on SIV Disease Progression in the Rhesus Macaque (Macaca mulatta) Model

“…Other alleles such as Mamu-A1*02 , Mamu-A1*08 , Mamu-A1*011 , Mamu-B*01 , Mamu-B*03 , and Mamu-B*04 have been implicated in the restriction of SIV or SHIV CD8 + T-cell epitopes. Additionally, Mamu-A*07 may have a potential role in the immune response against SIV [31]. MHC class II alleles Mamu-DRB1*0306 and Mamu-DRB1*1003 have been shown to be highly expressed in elite controllers and to contribute to reducing SIV viral load along with Mamu -B*17 -positive animals [21].…”