ABSTRACT
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.
Subject(s)
Haplotypes , Histocompatibility Antigens Class I/genetics , Simian Acquired Immunodeficiency Syndrome/genetics , Simian Immunodeficiency Virus/immunology , Alleles , Animals , Cohort Studies , Disease Progression , Gene Frequency , Histocompatibility Antigens Class I/immunology , Macaca mulatta , Simian Acquired Immunodeficiency Syndrome/immunology , Statistics as Topic , Survival AnalysisABSTRACT
Cynomolgus macaques are frequently used in biomedical research. However, in contrast to their closest relative, the rhesus macaque, little is known about their Mhc genes except for the DQB1 locus. In this study, 33 DRB-sequences belonging to 17 allelic lineages were detected in a total of 68 macaques, 58 originating from Mauritius and 10 from China. The majority of the sequences were detected in the few macaques from China, confirming the low degree of genetic variation in macaques from Mauritius. In summary, the DRB region in cynomolgus macaques is polymorphic. The sequences belong in general to the same allelic lineages as in their closest relative, the rhesus macaque. Two exon 2 DNA sequences were identical in both species and may represent a trans-species origin. In addition, protein sequences of members of the DRB*W1 lineage seem to be rather conserved in the three macaque species examined so far. Six DRB-haplotypes were detected in the macaques from Mauritius. While single DRB-alleles or some protein sequences seemed to be conserved among macaque species, we could not detect any evidence for a trans-species conservation of a complete DRB region. Overall, the data indicate that reorganization of the DRB region by recombination is a major force in creating diversity in cynomolgus macaques as it is in rhesus macaques.
