AIDS Animal Models: Cellular Immunology and Immunogenetics

National Institute Of Allergy And Infectious Diseases

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Abstract

Studies in humans and in macaques have demonstrated that CD8+ T cells responses are associated with the initial control of HIV or SIV replication. Specific major histocompatibility complex (MHC) genotypes have been found to be associated with lower viral loads and slower disease progression. However the exact correlates of protection remain unidentified and cellular immune responses required for an effective vaccine need to be defined. Crucial information can be obtained from experimental models of infection such as infection of Asian macaques with SIV or SHIV viruses, but also from studies of natural hosts of SIVs, such as African green monkeys, which exhibit high viral loads but remain disease-free. Comparison of immune responses induced in these natural hosts and in Asian macaques infected with the same SIV strains would shed light on the protective mechanisms used by African primates to resist the development of immunodeficiency. Three macaque species are used to mimic HIV infection in pathogenesis and vaccine studies, namely rhesus macaques (Macaca mulatta), pig-tailed macaques (M. nemestrina) and cynomolgus monkeys (M. fascicularis). Rhesus macaques are currently the principal non-human primate species used for virologic and immunologic studies. Pig-tailed macaques possess particular susceptibility and disease development characteristics that make this species informative for AIDS research. When infected with SIVagm, pig-tailed macaques maintain high plasma viral loads and develop AIDS-like symptoms, whereas rhesus monkeys, challenged with the same virus, control virus replication to undetectable levels and do not develop disease. Macaques infected with SIV develop AIDS-like disease within a variable time frame, similarly to the disease course in HIV-infected humans. In these settings, the variability in pathogenesis development is not related to the amount of virus inoculated, suggesting that host-specific immunologic and genetic factors play a significant role. Specific MHC class I alleles have been associated with slower disease progression and lower viral loads in humans and in macaques (HLA-B*57 in humans, Mamu-A*01 and Mamu-B*17 in rhesus macaques). A similar link between MHC genetic background and disease course has not been established for pig-tailed macaques. Furthermore the organization of MHC class I genes in the African green monkeys remains unknown.[unreadable] [unreadable] We previously analyzed the MHC class I genes in pig-tailed macaques. We identified 19 classical MHC class I alleles and found that MHC-A and MHC-B loci were duplicated at least once in pig-tailed macaques and no MHC-C locus was detected. This first study performed on in a small cohort of individual pig-tailed macaques revealed the existence of three different MHC-A haplotypes. We have expanded our analysis of MHC-A loci present in the genome of pig-tailed macaques to a larger group of animals revealing that the MHC-A region is very complex in this species. Five Mane-A loci were detected including a highly polymorphic Mane-A1 locus and four oligomorphic loci named Mane-A2, -A3, -A4 and -A6 that are orthologues of MHC-A loci detected in rhesus and cynomolgus macaques. The Mane-A2 locus is present at high frequency (90%) in pig-tailed macaques and encodes an oligomorphic family of alleles (Mane-A*06 family) that are expressed at low levels. The Mane-A3 and -A4 loci encode oligomorphic allele families represented by Mane-A*20 and Mane-A*17 in pig-tailed macaques. Interestingly, one allele encoded by the Mane-A3 locus (Mane-A*20) is shared between three macaque species. Additionally, a fifth MHC-A locus, previously undetected in Indian rhesus macaques, was shown to encode an oligomorphic family of alleles (Mane-A*09 family). All oligomorphic Mane-A loci are not always present in the pig-tailed macaque genome and the combination of the 5 Mane-A loci appears to be variable within a population of pig-tailed macaques. Using pedigree analysis we were able to identify six MHC-A configurations carrying a variable number of MHC-A loci (between two to four Mane-A loci). During the course of this study, we have developed molecular tools that are used for MHC typing of pig-tailed macaques. We have also identified CD8+ T cell responses specific for a SIV p27 Gag peptide (HR9 HQAAMQIIR) in several SHIV infected pig-tailed macaques. After inoculation, these animals controlled viral replication and have remained asymptomatic for up to 6 years with undetectable levels of plasma viral RNA. Other similarly inoculated macaques experienced a complete and irreversible elimination of their CD4+ T cells and had to be euthanized within 6 months post infection. We have found that these responses were restricted by the Mane-A*03 allele.