title: Escape in one of two cytotoxic T-lymphocyte epitopes bound by a high-frequency major histocompatibility complex class I molecule, Mamu-A*02: a paradigm for virus evolution and persistence?
abstract: It is now accepted that an effective vaccine against AIDS must include effective cytotoxic-T-lymphocyte (CTL) responses. The simian immunodeficiency virus (SIV)-infected rhesus macaque is the best available animal model for AIDS, but analysis of macaque CTL responses has hitherto focused mainly on epitopes bound by a single major histocompatibility complex (MHC) class I molecule, Mamu-A*01. The availability of Mamu-A*01-positive macaques for vaccine studies is therefore severely limited. Furthermore, it is becoming clear that different CTL responses are able to control immunodeficiency virus replication with varying success, making it a priority to identify and analyze CTL responses restricted by common MHC class I molecules other than Mamu-A*01. Here we describe two novel epitopes derived from SIV, one from Gag (Gag(71-79) GY9), and one from the Nef protein (Nef(159-167) YY9). Both epitopes are bound by the common macaque MHC class I molecule, Mamu-A*02. The sequences of these two eptiopes are consistent with the molecule's peptide-binding motif, which we have defined by elution of natural ligands from Mamu-A*02. Strikingly, we found evidence for the selection of escape variant viruses by CTL specific for Nef(159-167) YY9 in 6 of 6 Mamu-A*02-positive animals. In contrast, viral sequences encoding the Gag(71-79) GY9 epitope remained intact in each animal. This situation is reminiscent of Mamu-A*01-restricted CTL that recognize Tat(28-35) SL8, which reproducibly selects for escape variants during acute infection, and Gag(181-189) CM9, which does not. Differential selection by CTL may therefore be a paradigm of immunodeficiency virus infection.
authors.affiliation: Wisconsin Regional Primate Research Center, University of Wisconsin, Madison, Wisconsin 53715, USA.
authors.forename: Thorsten U
authors.initials: TU
authors.lastname: Vogel
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Friedrich
authors.forename: David H
authors.initials: DH
authors.lastname: O'Connor
authors.forename: William
authors.initials: W
authors.lastname: Rehrauer
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Dodds
authors.forename: Heather
authors.initials: H
authors.lastname: Hickman
authors.forename: William
authors.initials: W
authors.lastname: Hildebrand
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.forename: Austin
authors.initials: A
authors.lastname: Hughes
authors.forename: Helen
authors.initials: H
authors.lastname: Horton
authors.forename: Kathy
authors.initials: K
authors.lastname: Vielhuber
authors.forename: Richard
authors.initials: R
authors.lastname: Rudersdorf
authors.forename: Ivna P
authors.initials: IP
authors.lastname: De Souza
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Reynolds
authors.forename: Todd M
authors.initials: TM
authors.lastname: Allen
authors.forename: Nancy
authors.initials: N
authors.lastname: Wilson
authors.forename: David I
authors.initials: DI
authors.lastname: Watkins
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D019143:Evolution, Molecular; D015683:Gene Products, gag / Q000276:immunology; D015693:Gene Products, nef / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D016056:Immunodominant Epitopes; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000235:genetics* / Q000254:growth & development* / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag; D015693:Gene Products, nef; D015395:Histocompatibility Antigens Class I; D016056:Immunodominant Epitopes; C089390:Mamu-A 02 antigen