title: Infection with "escaped" virus variants impairs control of simian immunodeficiency virus SIVmac239 replication in Mamu-B*08-positive macaques.
abstract: An understanding of the mechanism(s) by which some individuals spontaneously control human immunodeficiency virus (HIV)/simian immunodeficiency virus replication may aid vaccine design. Approximately 50% of Indian rhesus macaques that express the major histocompatibility complex (MHC) class I allele Mamu-B*08 become elite controllers after infection with simian immunodeficiency virus SIVmac239. Mamu-B*08 has a binding motif that is very similar to that of HLA-B27, a human MHC class I allele associated with the elite control of HIV, suggesting that SIVmac239-infected Mamu-B*08-positive (Mamu-B*08+) animals may be a good model for the elite control of HIV. The association with MHC class I alleles implicates CD8+ T cells and/or natural killer cells in the control of viral replication. We therefore introduced point mutations into eight Mamu-B*08-restricted CD8+ T-cell epitopes to investigate the contribution of epitope-specific CD8+ T-cell responses to the development of the control of viral replication. Ten Mamu-B*08+ macaques were infected with this mutant virus, 8X-SIVmac239. We compared immune responses and viral loads of these animals to those of wild-type SIVmac239-infected Mamu-B*08+ macaques. The five most immunodominant Mamu-B*08-restricted CD8+ T-cell responses were barely detectable in 8X-SIVmac239-infected animals. By 48 weeks postinfection, 2 of 10 8X-SIVmac239-infected Mamu-B*08+ animals controlled viral replication to <20,000 viral RNA (vRNA) copy equivalents (eq)/ml plasma, while 10 of 15 wild-type-infected Mamu-B*08+ animals had viral loads of <20,000 vRNA copy eq/ml (P = 0.04). Our results suggest that these epitope-specific CD8+ T-cell responses may play a role in establishing the control of viral replication in Mamu-B*08+ macaques.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Valentine
authors.forename: John T
authors.initials: JT
authors.lastname: Loffredo
authors.forename: Alex T
authors.initials: AT
authors.lastname: Bean
authors.forename: Enrique J
authors.initials: EJ
authors.lastname: León
authors.forename: Caitlin E
authors.initials: CE
authors.lastname: MacNair
authors.forename: Dominic R
authors.initials: DR
authors.lastname: Beal
authors.forename: Shari M
authors.initials: SM
authors.lastname: Piaskowski
authors.forename: Yann C
authors.initials: YC
authors.lastname: Klimentidis
authors.forename: Simon M
authors.initials: SM
authors.lastname: Lank
authors.forename: Roger W
authors.initials: RW
authors.lastname: Wiseman
authors.forename: Jason T
authors.initials: JT
authors.lastname: Weinfurter
authors.forename: Gemma E
authors.initials: GE
authors.lastname: May
authors.forename: Eva G
authors.initials: EG
authors.lastname: Rakasz
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Wilson
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Friedrich
authors.forename: David H
authors.initials: DH
authors.lastname: O'Connor
authors.forename: David B
authors.initials: DB
authors.lastname: Allison
authors.forename: David I
authors.initials: DI
authors.lastname: Watkins
mesh_terms: D000818:Animals; D002460:Cell Line; D017931:DNA Primers; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005805:Genes, MHC Class I / Q000276:immunology; D014644:Genetic Variation / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D008253:Macaca mulatta / Q000276:immunology / Q000821:virology; D016297:Mutagenesis, Site-Directed; D016097:Simian Acquired Immunodeficiency Syndrome / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000472:pathogenicity*; D019562:Viral Load; D014779:Virus Replication / Q000235:genetics*
chemical_list: D017931:DNA Primers; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I