title: Characteristics of HIV-1 Nef regions containing multiple CD8+ T cell epitopes: wealth of HLA-binding motifs and sensitivity to proteasome degradation.
abstract: First and foremost among the many factors that influence epitope presentation are the degradation of Ag, which results in peptide liberation, and the presence of HLA class I molecules able to present the peptides to T lymphocytes. To define the regions of HIV-1 Nef that can provide multiple T cell epitopes, we analyzed the Nef sequence and determined that there are 73 peptides containing 81 HLA-binding motifs. We tested the binding of these peptides to six common HLA molecules (HLA-A2, -A3, -A24, -B7, -B8, and -B35), and we showed that most of them were efficient binders (54% of motifs), especially peptides associating with HLA-A3, -B7/35, and -B8 molecules. Nef peptides most frequently recognized by T cells of HIV-1-infected individuals were 90-97, 135-143, 71-81, 77-85, 90-100, 73-82, and 128-137. The frequency of T cell recognition was not directly related to the strength of peptide-HLA binding. The generation of Nef epitopes is crucial; therefore, we investigated the digestion by the 20S proteasome of a large peptide, Nef(66-100). This fragment was efficiently cleaved, and NH(2)-terminally extended precursors of epitope 71-81 were recognized by T cells of an HIV-1-infected individual. These results suggest that a high frequency of T cell recognition may depend on proteasome cleavage.
authors.affiliation: Laboratoire d'Immunologie des Pathologies infectieuses et tumorales, Institut National de la Santé et de la Recherche Médicale, Unité 445, Institut Cochin de Génétique Moléculaire, Université René Descartes, Paris, France. choppin@cochin.inserm.fr
authors.forename: J
authors.initials: J
authors.lastname: Choppin
authors.forename: W
authors.initials: W
authors.lastname: Cohen
authors.forename: A
authors.initials: A
authors.lastname: Bianco
authors.forename: J P
authors.initials: JP
authors.lastname: Briand
authors.forename: F
authors.initials: F
authors.lastname: Connan
authors.forename: M
authors.initials: M
authors.lastname: Dalod
authors.forename: J G
authors.initials: JG
authors.lastname: Guillet
mesh_terms: D020816:Amino Acid Motifs / Q000276:immunology; D000595:Amino Acid Sequence; D017951:Antigen Presentation; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D002461:Cell Line, Transformed; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism*; D015693:Gene Products, nef / Q000276:immunology* / Q000378:metabolism*; D006679:HIV Seropositivity / Q000201:enzymology / Q000276:immunology; D015497:HIV-1 / Q000201:enzymology / Q000276:immunology*; D006680:HLA Antigens / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D016056:Immunodominant Epitopes / Q000378:metabolism; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000378:metabolism*; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding / Q000276:immunology; D054311:nef Gene Products, Human Immunodeficiency Virus
chemical_list: D018984:Epitopes, T-Lymphocyte; D015693:Gene Products, nef; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D016056:Immunodominant Epitopes; D009097:Multienzyme Complexes; D010446:Peptide Fragments; D054311:nef Gene Products, Human Immunodeficiency Virus; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex