Molecular Genetics Of Eukaryotic Cells And Their Viruses

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Abstract

Infections of macaques with simian immunodeficiency viruses (SIV) or chimeric simian human immunodeficiency viruses (SHIV) have been extensively used as animal models to study HIV pathogenesis and vaccine development. Although rhesus monkeys are currently the principal non-human primate species used, the differential susceptibility of Indian and Chinese rhesus macaque sub-species to SIV induced disease and the small number of animals having particular immunologic characteristics (e.g., the Mamu-A*01 allele), can profoundly influence the outcome and the interpretation of logistically demanding experiments. The two other macaque species, therefore, represent valid alternatives as animal models.[unreadable] [unreadable] The identification and characterization of genes involved in cellular immune responses, particularly the MHC class I genes, is currently a major goal for understanding how non-human primates control lentivirus replication. A better definition of macaque immunogenetics would allow the selection of more homogeneous groups of animals for pathogenesis and vaccine studies, and possibly reduce the variable clinical courses frequently observed in SIV or SHIV infected animals due to their non-inbred status. Improved characterization of macaque genetic make-up would also contribute to a deeper understanding of the kinetics of immune responses induced following immunization and/or infection. In contrast to the knowledge accumulated about the organization of the rhesus macaque MHC, investigations of the MHC class I genes of other macaque species have only recently begun. MHC class I alleles have been described for pig-tailed macaques and cynomolgus monkeys. Nothing is currently known about the organization of the MHC class I region in pig-tailed macaques nor the similarities or orthology of their loci with the rhesus and cynomolgus macaque loci.[unreadable] [unreadable] Focusing on the MHC-A alleles of pig-tailed macaques, we have found that the gene expressing the Mane-A*06 allele of pig-tailed macaques is an orthologue of the locus encoding the Mamu-A*05 allele family in rhesus macaques. Analysis of the distribution of this locus in a cohort of 63 pig-tailed macaques revealed that it encodes an oligomorphic family of alleles, highly prevalent (90%) in the pig-tailed macaque population. Similarly, this locus was very frequently found (62%) in a cohort of 80 Indian rhesus macaques. An orthologous gene was also detected in cynomolgus monkeys originating from four different geographical locations, but was absent in two African monkey species. Expression analysis in pig-tailed macaques revealed that the Mane-A*06 alleles encoded by this locus are transcribed at 10 to 20- fold lower levels than other MHC-A alleles (Mane-A*03 or Mane-A*10). Despite their conservation and high prevalence among Asian macaque species, the alleles of the Mane-A*06 family and, by extension their orthologues in rhesus and cynomolgus monkeys, may only modestly contribute to cellular immune responses in macaques because of their low level of expression.