title: Generation of robust CD8+ T-cell responses against subdominant epitopes in conserved regions of HIV-1 by repertoire mining with mimotopes.
abstract: HLA-A 0201-restricted virus-specific CD8(+) CTL do not appear to control HIV effectively in vivo. To enhance the immunogenicity of a highly conserved subdominant epitope, TV9 (TLNAWVKVV, p24 Gag(19-27)), mimotopes were designed by screening a large combinatorial nonapeptide library with TV9-specific CTL primed in vitro from healthy donors. A mimic peptide with a low binding affinity to HLA-A 0201, TV9p6 (KINAWIKVV), was studied further. Parallel cultures of in vitro-primed CTL showed that TV9p6 consistently activated cross-reactive and equally functional CTL as measured by cytotoxicity, cytokine production and suppression of HIV replication in vitro. Comparison of TCRB gene usage between CTL primed from the same donors with TV9 or TV9p6 revealed a degree of clonal overlap in some cases and an example of a conserved TCRB sequence encoded distinctly at the nucleotide level between individuals (a "public" TCR); however, in the main, distinct clonotypes were recruited by each peptide antigen. These findings indicate that mimotopes can mobilize functional cross-reactive clonotypes that are less readily recruited from the naïve T-cell pool by the corresponding WT epitope. Mimotope-induced repertoire diversification could potentially override subdominance under certain circumstances and enhance vaccine-induced responses to conserved but poorly immunogenic determinants within the HIV proteome.
authors.affiliation: Department of Biological Sciences and Border Biomedical Research Institute, University of Texas at El Paso, El Paso, TX, USA.
authors.forename: Keri L
authors.initials: KL
authors.lastname: Schaubert
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Janelle R
authors.initials: JR
authors.lastname: Salkowitz
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Sewell
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.forename: Tedi E
authors.initials: TE
authors.lastname: Asher
authors.forename: Sylvie E
authors.initials: SE
authors.lastname: Blondelle
authors.forename: Sharon
authors.initials: S
authors.lastname: Adams
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Marincola
authors.forename: Aviva
authors.initials: A
authors.lastname: Joseph
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.forename: Velpandi
authors.initials: V
authors.lastname: Ayyavoo
authors.forename: Walter
authors.initials: W
authors.lastname: Storkus
authors.forename: Ming-Ying
authors.initials: MY
authors.lastname: Leung
authors.forename: Hwee L
authors.initials: HL
authors.lastname: Ng
authors.forename: Otto O
authors.initials: OO
authors.lastname: Yang
authors.forename: Harris
authors.initials: H
authors.lastname: Goldstein
authors.forename: Darcy B
authors.initials: DB
authors.lastname: Wilson
authors.forename: June
authors.initials: J
authors.lastname: Kan-Mitchell
mesh_terms: D016915:AIDS Vaccines; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002999:Clone Cells; D017124:Conserved Sequence / Q000235:genetics; D004247:DNA / Q000032:analysis*; D018604:Epitope Mapping; D016655:HIV Core Protein p24 / Q000737:chemistry / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology*; D015234:HLA-A Antigens / Q000378:metabolism; D015789:HLA-A2 Antigen; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D019151:Peptide Library; D011485:Protein Binding; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*
chemical_list: D016915:AIDS Vaccines; D016655:HIV Core Protein p24; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D010446:Peptide Fragments; D019151:Peptide Library; D016693:Receptors, Antigen, T-Cell, alpha-beta; C514799:p24 protein, Human Immunodeficiency Virus Type 1; D004247:DNA