title: Linking pig-tailed macaque major histocompatibility complex class I haplotypes and cytotoxic T lymphocyte escape mutations in simian immunodeficiency virus infection.
abstract: The 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.
  
  
  OBJECTIVE
  Cytotoxic 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.
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Shayarana L
authors.initials: SL
authors.lastname: Gooneratne
authors.affiliation: Centre for Vascular Research, UNSW Australia, Kensington, New South Wales, Australia.
authors.forename: Hamid
authors.initials: H
authors.lastname: Alinejad-Rokny
authors.affiliation: Centre for Vascular Research, UNSW Australia, Kensington, New South Wales, Australia.
authors.forename: Diako
authors.initials: D
authors.lastname: Ebrahimi
authors.affiliation: Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Bohn
authors.affiliation: Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Roger W
authors.initials: RW
authors.lastname: Wiseman
authors.affiliation: Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: O'Connor
authors.affiliation: Centre for Vascular Research, UNSW Australia, Kensington, New South Wales, Australia.
authors.forename: Miles P
authors.initials: MP
authors.lastname: Davenport
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia skent@unimelb.edu.au.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kent
mesh_terms: D000818:Animals; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D006239:Haplotypes; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D057131:Immune Evasion; D008254:Macaca nemestrina; D020125:Mutation, Missense; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000145:classification / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I