Availability of a diversely avid CD8+ T cell repertoire specific for the subdominant HLA-A2-restricted HIV-1 Gag p2419-27 epitope

Keri L. Schaubert, David A. Price, Nicole Frahm, Jinzhu Li, Hwee L. Ng, Aviva Joseph, Elyse Paul, Biswanath Majumder, Velpandi Ayyavoo, Emma Gostick, Sharon Adams, Francesco M. Marincola, Andrew K. Sewell, Marcus Altfeld, Jason M. Brenchley, Daniel C. Douek, Otto O. Yang, Christian Brander, Harris Goldstein, June Kan-Mitchell

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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 p2419-27, 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.

Original languageEnglish (US)
Pages (from-to)7756-7766
Number of pages11
JournalJournal of Immunology
Volume178
Issue number12
StatePublished - Jun 15 2007

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HLA-A2 Antigen
HIV-1
Epitopes
T-Lymphocytes
Dendritic Cells
Population
HIV Infections
Tissue Donors
Viruses

ASJC Scopus subject areas

  • Immunology

Cite this

Schaubert, K. L., Price, D. A., Frahm, N., Li, J., Ng, H. L., Joseph, A., ... Kan-Mitchell, J. (2007). Availability of a diversely avid CD8+ T cell repertoire specific for the subdominant HLA-A2-restricted HIV-1 Gag p2419-27 epitope. Journal of Immunology, 178(12), 7756-7766.

Availability of a diversely avid CD8+ T cell repertoire specific for the subdominant HLA-A2-restricted HIV-1 Gag p2419-27 epitope. / Schaubert, Keri L.; Price, David A.; Frahm, Nicole; Li, Jinzhu; Ng, Hwee L.; Joseph, Aviva; Paul, Elyse; Majumder, Biswanath; Ayyavoo, Velpandi; Gostick, Emma; Adams, Sharon; Marincola, Francesco M.; Sewell, Andrew K.; Altfeld, Marcus; Brenchley, Jason M.; Douek, Daniel C.; Yang, Otto O.; Brander, Christian; Goldstein, Harris; Kan-Mitchell, June.

In: Journal of Immunology, Vol. 178, No. 12, 15.06.2007, p. 7756-7766.

Research output: Contribution to journalArticle

Schaubert, KL, Price, DA, Frahm, N, Li, J, Ng, HL, Joseph, A, Paul, E, Majumder, B, Ayyavoo, V, Gostick, E, Adams, S, Marincola, FM, Sewell, AK, Altfeld, M, Brenchley, JM, Douek, DC, Yang, OO, Brander, C, Goldstein, H & Kan-Mitchell, J 2007, 'Availability of a diversely avid CD8+ T cell repertoire specific for the subdominant HLA-A2-restricted HIV-1 Gag p2419-27 epitope', Journal of Immunology, vol. 178, no. 12, pp. 7756-7766.
Schaubert, Keri L. ; Price, David A. ; Frahm, Nicole ; Li, Jinzhu ; Ng, Hwee L. ; Joseph, Aviva ; Paul, Elyse ; Majumder, Biswanath ; Ayyavoo, Velpandi ; Gostick, Emma ; Adams, Sharon ; Marincola, Francesco M. ; Sewell, Andrew K. ; Altfeld, Marcus ; Brenchley, Jason M. ; Douek, Daniel C. ; Yang, Otto O. ; Brander, Christian ; Goldstein, Harris ; Kan-Mitchell, June. / Availability of a diversely avid CD8+ T cell repertoire specific for the subdominant HLA-A2-restricted HIV-1 Gag p2419-27 epitope. In: Journal of Immunology. 2007 ; Vol. 178, No. 12. pp. 7756-7766.
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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 p2419-27, 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.",
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AU - Frahm, Nicole

AU - Li, Jinzhu

AU - Ng, Hwee L.

AU - Joseph, Aviva

AU - Paul, Elyse

AU - Majumder, Biswanath

AU - Ayyavoo, Velpandi

AU - Gostick, Emma

AU - Adams, Sharon

AU - Marincola, Francesco M.

AU - Sewell, Andrew K.

AU - Altfeld, Marcus

AU - Brenchley, Jason M.

AU - Douek, Daniel C.

AU - Yang, Otto O.

AU - Brander, Christian

AU - Goldstein, Harris

AU - Kan-Mitchell, June

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N2 - 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 p2419-27, 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.

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