title: The presence of prolines in the flanking region of an immunodominant HIV-2 gag epitope influences the quality and quantity of the epitope generated.
abstract: Both the recognition of HIV-infected cells and the immunogenicity of candidate CTL vaccines depend on the presentation of a peptide epitope at the cell surface, which in turn depends on intracellular antigen processing. Differential antigen processing maybe responsible for the differences in both the quality and the quantity of epitopes produced, influencing the immunodominance hierarchy of viral epitopes. Previously, we showed that the magnitude of the HIV-2 gag-specific T-cell response is inversely correlated with plasma viral load, particularly when responses are directed against an epitope, 165 DRFYKSLRA173 , within the highly conserved Major Homology Region of gag-p26. We also showed that the presence of three proline residues, at positions 119, 159 and 178 of gag-p26, was significantly correlated with low viral load. Since this proline motif was also associated with stronger gag-specific CTL responses, we investigated the impact of these prolines on proteasomal processing of the protective 165 DRFYKSLRA173 epitope. Our data demonstrate that the 165 DRFYKSLRA173 epitope is most efficiently processed from precursors that contain two flanking proline residues, found naturally in low viral-load patients. Superior antigen processing and enhanced presentation may account for the link between infection with HIV-2 encoding the "PPP-gag" sequence and both strong gag-specific CTL responses as well as lower viral load.
authors.affiliation: Radcliffe Department of Medicine, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headington, Oxford, UK.
authors.forename: Sabelle
authors.initials: S
authors.lastname: Jallow
authors.affiliation: Interdepartmental Division of Critical Care Medicine, University of Toronto, Canada.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Leligdowicz
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Holger B
authors.initials: HB
authors.lastname: Kramer
authors.affiliation: Medical Research Council Unit, Fajara, The Gambia.
authors.forename: Clayton
authors.initials: C
authors.lastname: Onyango
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Cotten
authors.affiliation: Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford, UK.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Wright
authors.affiliation: Medical Research Council Unit, Fajara, The Gambia.
authors.forename: Hilton C
authors.initials: HC
authors.lastname: Whittle
authors.affiliation: Radcliffe Department of Medicine, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headington, Oxford, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: McMichael
authors.affiliation: Radcliffe Department of Medicine, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Headington, Oxford, UK.
authors.forename: Tao
authors.initials: T
authors.lastname: Dong
authors.affiliation: Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford, UK.
authors.forename: Benedikt M
authors.initials: BM
authors.lastname: Kessler
authors.affiliation: Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford, UK.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Rowland-Jones
mesh_terms: D020816:Amino Acid Motifs; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005260:Female; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015498:HIV-2 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D008297:Male; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D019562:Viral Load / Q000276:immunology; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D054301:gag Gene Products, Human Immunodeficiency Virus
keywords: Antigen processing; CTL epitopes; DRFYKSLRA; Gag p26; HIV-2