title: Novel and promiscuous CTL epitopes in conserved regions of Gag targeted by individuals with early subtype C HIV type 1 infection from southern Africa.
abstract: Characterization of optimal CTL epitopes in Gag can provide crucial information for evaluation of candidate vaccines in populations at the epicenter of the HIV-1 epidemic. We screened 38 individuals with recent subtype C HIV-1 infection using overlapping consensus C Gag peptides and hypothesized that unique HLA-restricting alleles in the southern African population would determine novel epitope identity. Seventy-four percent of individuals recognized at least one Gag peptide pool. Ten epitopic regions were identified across p17, p24, and p2p7p1p6, and greater than two-thirds of targeted regions were directed at: TGTEELRSLYNTVATLY (p17, 35%); GPKEPFRDYVDRFFKTLRAEQATQDV (p24, 19%); and RGGKLDKWEKIRLRPGGKKHYMLKHL (p17, 15%). After alignment of these epitopic regions with consensus M and a consensus subtype C sequence from the cohort, it was evident that the regions targeted were highly conserved. Fine epitope mapping revealed that five of nine identified optimal Gag epitopes were novel: HLVWASREL, LVWASRELERF, LYNTVATLY, PFRDYVDRFF, and TLRAEQATQD, and were restricted by unique HLA-Cw*08, HLA-A*30/B*57, HLA-A*29/B*44, and HLA-Cw*03 alleles, respectively. Notably, three of the mapped epitopes were restricted by more than one HLA allele. Although these epitopes were novel and restricted by unique HLA, they overlapped or were embedded within previously described CTL epitopes from subtype B HIV-1 infection. These data emphasize the promiscuous nature of epitope binding and support our hypothesis that HLA diversity between populations can shape fine epitope identity, but may not represent a constraint for universal recognition of Gag in highly conserved domains.
authors.affiliation: National Institute for Communicable Diseases, University of Witwatersrand, Johannesburg, South Africa.
authors.forename: Agatha M
authors.initials: AM
authors.lastname: Masemola
authors.forename: Tumelo N
authors.initials: TN
authors.lastname: Mashishi
authors.forename: Greg
authors.initials: G
authors.lastname: Khoury
authors.forename: Helba
authors.initials: H
authors.lastname: Bredell
authors.forename: Maria
authors.initials: M
authors.lastname: Paximadis
authors.forename: Tiyani
authors.initials: T
authors.lastname: Mathebula
authors.forename: Debra
authors.initials: D
authors.lastname: Barkhan
authors.forename: Adrian
authors.initials: A
authors.lastname: Puren
authors.forename: Efthyia
authors.initials: E
authors.lastname: Vardas
authors.forename: Mark
authors.initials: M
authors.lastname: Colvin
authors.forename: Lynn
authors.initials: L
authors.lastname: Zijenah
authors.forename: David
authors.initials: D
authors.lastname: Katzenstein
authors.forename: Rosemary
authors.initials: R
authors.lastname: Musonda
authors.forename: Susan
authors.initials: S
authors.lastname: Allen
authors.forename: Newton
authors.initials: N
authors.lastname: Kumwenda
authors.forename: Taha
authors.initials: T
authors.lastname: Taha
authors.forename: Glenda
authors.initials: G
authors.lastname: Gray
authors.forename: James
authors.initials: J
authors.lastname: McIntyre
authors.forename: Salim Abdool
authors.initials: SA
authors.lastname: Karim
authors.forename: Haynes W
authors.initials: HW
authors.lastname: Sheppard
authors.forename: Clive M
authors.initials: CM
authors.lastname: Gray
mesh_terms: D000353:Africa, Southern; D000595:Amino Acid Sequence; D002461:Cell Line, Transformed; D017124:Conserved Sequence; D003602:Cytotoxicity, Immunologic; D018604:Epitope Mapping / Q000379:methods; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism*; D015683:Gene Products, gag / Q000276:immunology* / Q000378:metabolism*; D015488:HIV Antigens / Q000276:immunology / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006650:Histocompatibility Testing; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D017434:Protein Structure, Tertiary; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014764:Viral Proteins / Q000276:immunology / Q000378:metabolism; D054301:gag Gene Products, Human Immunodeficiency Virus
chemical_list: D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag; D015488:HIV Antigens; D010446:Peptide Fragments; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; C054858:p17 protein, Human Immunodeficiency Virus Type 1