Novel and promiscuous CTL epitopes in conserved regions of Gag targeted by individuals with early subtype C HIV type 1 infection from southern Africa.
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.
Masemola
Agatha M
AM
National Institute for Communicable Diseases, University of Witwatersrand, Johannesburg, South Africa.
Mashishi
Tumelo N
TN
Khoury
Greg
G
Bredell
Helba
H
Paximadis
Maria
M
Mathebula
Tiyani
T
Barkhan
Debra
D
Puren
Adrian
A
Vardas
Efthyia
E
Colvin
Mark
M
Zijenah
Lynn
L
Katzenstein
David
D
Musonda
Rosemary
R
Allen
Susan
S
Kumwenda
Newton
N
Taha
Taha
T
Gray
Glenda
G
McIntyre
James
J
Karim
Salim Abdool
SA
Sheppard
Haynes W
HW
Gray
Clive M
CM
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
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