title: Availability of a diversely avid CD8+ T cell repertoire specific for the subdominant HLA-A2-restricted HIV-1 Gag p2419-27 epitope.
abstract: HLA-A2-restricted CTL responses to immunodominant HIV-1 epitopes do not appear to be very effective in the control of viral replication in vivo. In this study, we studied human CD8+ T cell responses to the subdominant HLA-A2-restricted epitope TV9 (Gag p24(19-27), TLNAWVKVV) to explore the possibility of increasing its immune recognition. We confirmed in a cohort of 313 patients, infected by clade B or clade C viruses, that TV9 is rarely recognized. Of interest, the functional sensitivity of the TV9 response can be relatively high. The potential T cell repertoires for TV9 and the characteristics of constituent clonotypes were assessed by ex vivo priming of circulating CD8+ T cells from healthy seronegative donors. TV9-specific CTLs capable of suppressing viral replication in vitro were readily generated, suggesting that the cognate T cell repertoire is not limiting. However, these cultures contained multiple discrete populations with a range of binding avidities for the TV9 tetramer and correspondingly distinct functional dependencies on the CD8 coreceptor. The lack of dominant clonotypes was not affected by the stage of maturation of the priming dendritic cells. Cultures primed by dendritic cells transduced to present endogenous TV9 were also incapable of clonal maturation. Thus, a diffuse TCR repertoire appeared to be an intrinsic characteristic of TV9-specific responses. These data indicate that subdominance is not a function of poor immunogenicity, cognate TCR repertoire availability, or the potential avidity properties thereof, but rather suggest that useful responses to this epitope are suppressed by competing CD8+ T cell populations during HIV-1 infection.
authors.affiliation: Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Keri L
authors.initials: KL
authors.lastname: Schaubert
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Nicole
authors.initials: N
authors.lastname: Frahm
authors.forename: Jinzhu
authors.initials: J
authors.lastname: Li
authors.forename: Hwee L
authors.initials: HL
authors.lastname: Ng
authors.forename: Aviva
authors.initials: A
authors.lastname: Joseph
authors.forename: Elyse
authors.initials: E
authors.lastname: Paul
authors.forename: Biswanath
authors.initials: B
authors.lastname: Majumder
authors.forename: Velpandi
authors.initials: V
authors.lastname: Ayyavoo
authors.forename: Emma
authors.initials: E
authors.lastname: Gostick
authors.forename: Sharon
authors.initials: S
authors.lastname: Adams
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Marincola
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Sewell
authors.forename: Marcus
authors.initials: M
authors.lastname: Altfeld
authors.forename: Jason M
authors.initials: JM
authors.lastname: Brenchley
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.forename: Otto O
authors.initials: OO
authors.lastname: Yang
authors.forename: Christian
authors.initials: C
authors.lastname: Brander
authors.forename: Harris
authors.initials: H
authors.lastname: Goldstein
authors.forename: June
authors.initials: J
authors.lastname: Kan-Mitchell
mesh_terms: D000595:Amino Acid Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D003429:Cross Reactions; D003713:Dendritic Cells / Q000276:immunology; D015683:Gene Products, gag / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D015683:Gene Products, gag; D015789:HLA-A2 Antigen; D016056:Immunodominant Epitopes; D011948:Receptors, Antigen, T-Cell