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Characterization of Mauritian cynomolgus macaque major histocompatibility complex class I haplotypes by high-resolution pyrosequencing.

ABSTRACT: Major histocompatibility complex (MHC) class I alleles of nonhuman primates have been associated with disease susceptibility, resistance, and resolution. Here, using high-resolution pyrosequencing, we characterized MHC class I transcripts expressed in Mauritian cynomolgus macaques (MCM), a nonhuman primate population with restricted MHC diversity. Using this approach, we identified 67 distinct MHC class I transcripts encoded by the seven most frequent MCM MHC class I haplotypes, 40 (60%) of which span the complete open reading frames. These results double the number of MHC class I sequences previously defined by cloning and Sanger sequencing of cDNA-PCR products and provide a rapid, high-throughput, and economical method for MHC characterization. Overall, this approach significantly expanded our knowledge of MCM haplotypes and will facilitate future studies on disease pathogenesis and protective cellular immunity.

SUBMITTER: Budde ML

PROVIDER: S-EPMC3077881 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Characterization of Mauritian cynomolgus macaque major histocompatibility complex class I haplotypes by high-resolution pyrosequencing.

Budde Melisa L ML Wiseman Roger W RW Karl Julie A JA Hanczaruk Bozena B Simen Birgitte B BB O'Connor David H DH

Immunogenetics 20100930 11-12

Major histocompatibility complex (MHC) class I alleles of nonhuman primates have been associated with disease susceptibility, resistance, and resolution. Here, using high-resolution pyrosequencing, we characterized MHC class I transcripts expressed in Mauritian cynomolgus macaques (MCM), a nonhuman primate population with restricted MHC diversity. Using this approach, we identified 67 distinct MHC class I transcripts encoded by the seven most frequent MCM MHC class I haplotypes, 40 (60%) of whic ...[more]

PMID: 20882385

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Project description:UnlabelledThe influence of major histocompatibility complex class I (MHC-I) alleles on human immunodeficiency virus (HIV) diversity in humans has been well characterized at the population level. MHC-I alleles likely affect viral diversity in the simian immunodeficiency virus (SIV)-infected pig-tailed macaque (Macaca nemestrina) model, but this is poorly characterized. We studied the evolution of SIV in pig-tailed macaques with a range of MHC-I haplotypes. SIV(mac251) genomes were amplified from the plasma of 44 pig-tailed macaques infected with SIV(mac251) at 4 to 10 months after infection and characterized by Illumina deep sequencing. MHC-I typing was performed on cellular RNA using Roche/454 pyrosequencing. MHC-I haplotypes and viral sequence polymorphisms at both individual mutations and groups of mutations spanning 10-amino-acid segments were linked using in-house bioinformatics pipelines, since cytotoxic T lymphocyte (CTL) escape can occur at different amino acids within the same epitope in different animals. The approach successfully identified 6 known CTL escape mutations within 3 Mane-A1*084-restricted epitopes. The approach also identified over 70 new SIV polymorphisms linked to a variety of MHC-I haplotypes. Using functional CD8 T cell assays, we confirmed that one of these associations, a Mane-B028 haplotype-linked mutation in Nef, corresponded to a CTL epitope. We also identified mutations associated with the Mane-B017 haplotype that were previously described to be CTL epitopes restricted by Mamu-B*017:01 in rhesus macaques. This detailed study of pig-tailed macaque MHC-I genetics and SIV polymorphisms will enable a refined level of analysis for future vaccine design and strategies for treatment of HIV infection.ImportanceCytotoxic T lymphocytes select for virus escape mutants of HIV and SIV, and this limits the effectiveness of vaccines and immunotherapies against these viruses. Patterns of immune escape variants are similar in HIV type 1-infected human subjects that share the same MHC-I genes, but this has not been studied for SIV infection of macaques. By studying SIV sequence diversity in 44 MHC-typed SIV-infected pigtail macaques, we defined over 70 sites within SIV where mutations were common in macaques sharing particular MHC-I genes. Further, pigtail macaques sharing nearly identical MHC-I genes with rhesus macaques responded to the same CTL epitope and forced immune escape. This allows many reagents developed to study rhesus macaques to also be used to study pigtail macaques. Overall, our study defines sites of immune escape in SIV in pigtailed macaques, and this enables a more refined level of analysis of future vaccine design and strategies for treatment of HIV infection.

Dataset Information

Characterization of Mauritian cynomolgus macaque major histocompatibility complex class I haplotypes by high-resolution pyrosequencing.

Publications

Characterization of Mauritian cynomolgus macaque major histocompatibility complex class I haplotypes by high-resolution pyrosequencing.

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