Characterization of Pig-Tailed Macaque Classical MHC Class I Genes: Implications for MHC Evolution and Antigen Presentation in Macaques

Abstract

MHC-dependent CD8+ T cell responses have been associated with control of viral replication and slower disease progression during lentiviral infections. Pig-tailed macaques (Macaca nemestrina) and rhesus monkeys (Macaca mulatta), two nonhuman primate species commonly used to model HIV infection, can exhibit distinct clinical courses after infection with different primate lentiviruses. As an initial step in assessing the role of MHC class I restricted immune responses to these infections, we have cloned and characterized classical MHC class I genes of pig-tailed macaques and have identified 19 MHC class I alleles (Mane) orthologous to rhesus macaque MHC-A, -B, and -I genes. Both Mane-A and Mane-B loci were found to be duplicated, and no MHC-C locus was detected. Pig-tailed and rhesus macaque MHC-A alleles form two groups, as defined by 14 polymorphisms affecting mainly their B peptide-binding pockets. Furthermore, an analysis of multiple pig-tailed monkeys revealed the existence of three MHC-A haplotypes. The distribution of these haplotypes in various Old World monkeys provides new insights about MHC-A evolution in nonhuman primates. An examination of B and F peptide-binding pockets in rhesus and pig-tailed macaques suggests that their MHC-B molecules present few common peptides to their respective CTLs.

Analysis of Pigtail Macaque Major Histocompatibility Complex Class I Molecules Presenting Immunodominant Simian Immunodeficiency Virus Epitopes

“…3, with the previously published Mane sequences provided for comparison. Up to two Mane-A and four Mane-B alleles were identified in each macaque, consistent with the observation that duplication of the Mane-B locus has occurred in this species (38), and similar to observations with rhesus macaques and baboons (1,14). It is likely that a less conservative method of allele definition would have resulted in more than two Mane-A alleles being detected in a single macaque, because this locus has previously been shown to be duplicated in M. nemestrina (38).…”

“…Up to two Mane-A and four Mane-B alleles were identified in each macaque, consistent with the observation that duplication of the Mane-B locus has occurred in this species (38), and similar to observations with rhesus macaques and baboons (1,14). It is likely that a less conservative method of allele definition would have resulted in more than two Mane-A alleles being detected in a single macaque, because this locus has previously been shown to be duplicated in M. nemestrina (38). Surprisingly, of the 18 pigtail macaque MHC class I alleles previously described (38), only two were detected in our cohort of macaques: Mane-B*02 in macaque 4247 and Mane-B*05 in macaque 4664.…”

“…It is likely that a less conservative method of allele definition would have resulted in more than two Mane-A alleles being detected in a single macaque, because this locus has previously been shown to be duplicated in M. nemestrina (38). Surprisingly, of the 18 pigtail macaque MHC class I alleles previously described (38), only two were detected in our cohort of macaques: Mane-B*02 in macaque 4247 and Mane-B*05 in macaque 4664. Variation between the newly defined alleles occurs in distinct regions of the peptide-binding (␣1 and ␣2) domains, particularly the regions spanning residues 9 to 25, 62 to 83, and 152 to 170.…”

“…A limited number of M. nemestrina (Mane) MHC class I alleles have been sequenced (38), though T-cell responses restricted by these alleles have not been identified. In this study, we describe the identification of a common, immunodominant response to KP9, a 9-mer Gag epitope in vaccinated pigtail macaques, and the characterization of its restricting MHC class I molecule, Mane-A*10.…”

Unusually High Frequency MHC Class I Alleles in Mauritian Origin Cynomolgus Macaques

“…We adopted a modified nomenclature for naming the newly discovered alleles that prioritizes amino acid identity in the ␣ 1 and ␣ 2 domains that control peptide binding and TCR recognition (37). Although previous nonhuman primate MHC I nomenclatures are based either on ad hoc, arbitrary designations of sequence novelty or concordance with serological data (25,27,38), the goal of the new nomenclature is to cluster alleles with identical peptide-binding domains within the same top-level domain. In this nomenclature, any nonsynonymous variation in the sequence encoding the ␣ 1 and ␣ 2 domains is given a new toplevel designation (e.g.…”