Mutually exclusive T-cell receptor induction and differential susceptibility to human immunodeficiency virus type 1 mutational escape associated with a two-amino-acid difference between HLA class I subtypes - PubMed (original) (raw)

. 2007 Feb;81(4):1619-31.

doi: 10.1128/JVI.01580-06. Epub 2006 Nov 22.

Mathias Lichterfeld, Senica Chetty, Katie L Williams, Stanley K Mui, Toshiyuki Miura, Nicole Frahm, Margaret E Feeney, Yanhua Tang, Florencia Pereyra, Montiago X Labute, Katja Pfafferott, Alisdair Leslie, Hayley Crawford, Rachel Allgaier, William Hildebrand, Richard Kaslow, Christian Brander, Todd M Allen, Eric S Rosenberg, Photini Kiepiela, Madhu Vajpayee, Paul A Goepfert, Marcus Altfeld, Philip J R Goulder, Bruce D Walker

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Mutually exclusive T-cell receptor induction and differential susceptibility to human immunodeficiency virus type 1 mutational escape associated with a two-amino-acid difference between HLA class I subtypes

Xu G Yu et al. J Virol. 2007 Feb.

Abstract

The relative contributions of HLA alleles and T-cell receptors (TCRs) to the prevention of mutational viral escape are unclear. Here, we examined human immunodeficiency virus type 1 (HIV-1)-specific CD8(+) T-cell responses restricted by two closely related HLA class I alleles, B*5701 and B*5703, that differ by two amino acids but are both associated with a dominant response to the same HIV-1 Gag epitope KF11 (KAFSPEVIPMF). When this epitope is presented by HLA-B*5701, it induces a TCR repertoire that is highly conserved among individuals, cross-recognizes viral epitope variants, and is rarely associated with mutational escape. In contrast, KF11 presented by HLA-B*5703 induces an entirely different, more heterogeneous TCR beta-chain repertoire that fails to recognize specific KF11 escape variants which frequently arise in clade C-infected HLA-B*5703(+) individuals. These data show the influence of HLA allele subtypes on TCR selection and indicate that extensive TCR diversity is not a prerequisite to prevention of allowable viral mutations.

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Figures

FIG. 1.

FIG. 1.

Frequency of KF11 mutations in HIV-1 clade B- and clade C-infected individuals. Data are from clade C-infected individuals recruited from South Africa and India (A) and from clade B-infected persons from the United States and Europe (B). (C) HIV-1 RNA of clade C-infected HLA-B*5703-expressing individuals with KF11 wt, A2G-S4(N/K), or A2(G/S/N) sequences.

FIG. 2.

FIG. 2.

Cross-recognition of KF11 peptide variants in HLA-B*5701- or -B*5703-expressing individuals. (A and B) KF11 variants with amino acid substitutions at position 2, positions 2 and 4, or positions 3, 5, 7, or 10 were tested for recognition in a representative person expressing HLA-B*5701 (A) or HLA-B*5703 (B). (C) Cross-recognition of KF11 variants with single position 2 or combined position 2 and 4 mutations in individuals expressing HLA-B*5701 (seven of the patients described in Table 2 for whom sufficient PBMC samples were available) or HLA-B*5703 (eight of the patients described in Table 2 for whom sufficient samples were available). *, no IFN-γ secretion was observed at the highest peptide concentration tested.

FIG. 3.

FIG. 3.

Presentation of KF11 peptide variants on HLA-B*5701- and -B*5703-expressing antigen-presenting cells. (A) Target cell lysis of HLA-B*5701- or -B*5703-expressing B-LCL pulsed with KF11 wild type or variant peptides following exposure to a KF11-specific CD8+ T-cell clone restricted to HLA-B*5701 (Vβ19-CASTGTYGYT-J1.2; Vα5-CAASGGYQKVTFGTGTKLQVIP). (B) Drop-off rate of KF11 peptide variants from HLA-B*5701- or -B*5703-expressing B-LCL. Target cell lysis of HLA-B*5701- or -B*5703-expressing B-LCL by an HLA-B*5701-restricted CD8+ T-cell clone was measured either immediately after peptide pulsing (0 h) or after 12 or 36 h of resting. One representative experiment out of three is shown. (C) Proliferative responses of B*5701- or B*5703-restricted KF11-specific CD8+ T cells to stimulation with KF11 wt or KF11 A2G-S4(N/K) peptides, as measured by CFSE dilution assays. The right column indicates proliferative responses of HLA-B*5701-restricted KF11-specific CD8+ T cells stimulated with KF11 wt peptide or KF11 A2G-S4(N/K) peptide presented by B*5703-restricted B-LCL.

FIG. 3.

FIG. 3.

Presentation of KF11 peptide variants on HLA-B*5701- and -B*5703-expressing antigen-presenting cells. (A) Target cell lysis of HLA-B*5701- or -B*5703-expressing B-LCL pulsed with KF11 wild type or variant peptides following exposure to a KF11-specific CD8+ T-cell clone restricted to HLA-B*5701 (Vβ19-CASTGTYGYT-J1.2; Vα5-CAASGGYQKVTFGTGTKLQVIP). (B) Drop-off rate of KF11 peptide variants from HLA-B*5701- or -B*5703-expressing B-LCL. Target cell lysis of HLA-B*5701- or -B*5703-expressing B-LCL by an HLA-B*5701-restricted CD8+ T-cell clone was measured either immediately after peptide pulsing (0 h) or after 12 or 36 h of resting. One representative experiment out of three is shown. (C) Proliferative responses of B*5701- or B*5703-restricted KF11-specific CD8+ T cells to stimulation with KF11 wt or KF11 A2G-S4(N/K) peptides, as measured by CFSE dilution assays. The right column indicates proliferative responses of HLA-B*5701-restricted KF11-specific CD8+ T cells stimulated with KF11 wt peptide or KF11 A2G-S4(N/K) peptide presented by B*5703-restricted B-LCL.

FIG. 4.

FIG. 4.

Presentation of naturally processed KF11 peptide variants on HLA-B*5701- and -B*5703-expressing B-LCL. IFN-γ secretion by the same HLA-B*5701-restricted KF11-specific CD8+ T-cell clone was analyzed after stimulation with HLA-B*5701- or -B*5703-expressing B-LCL infected with vaccinia virus constructs encoding different KF11 variant sequences. In each case, one representative example with an effector:target ratio of 10:1 is shown.

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References

    1. Allen, T. M., M. Altfeld, X. G. Yu, K. M. O'Sullivan, M. Lichterfeld, S. Le Gall, M. John, B. R. Mothe, P. K. Lee, E. T. Kalife, D. E. Cohen, K. A. Freedberg, D. A. Strick, M. N. Johnston, A. Sette, E. S. Rosenberg, S. A. Mallal, P. J. Goulder, C. Brander, and B. D. Walker. 2004. Selection, transmission, and reversion of an antigen-processing cytotoxic T-lymphocyte escape mutation in human immunodeficiency virus type 1 infection. J. Virol. 78:7069-7078. - PMC - PubMed
    1. Allen, T. M., D. H. O'Connor, P. Jing, J. L. Dzuris, B. R. Mothe, T. U. Vogel, E. Dunphy, M. E. Liebl, C. Emerson, N. Wilson, K. J. Kunstman, X. Wang, D. B. Allison, A. L. Hughes, R. C. Desrosiers, J. D. Altman, S. M. Wolinsky, A. Sette, and D. I. Watkins. 2000. Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia. Nature 407:386-390. - PubMed
    1. Argaet, V. P., C. W. Schmidt, S. R. Burrows, S. L. Silins, M. G. Kurilla, D. L. Doolan, A. Suhrbier, D. J. Moss, E. Kieff, T. B. Sculley, and I. S. Misko. 1994. Dominant selection of an invariant T cell antigen receptor in response to persistent infection by Epstein-Barr virus. J. Exp. Med. 180:2335-2340. - PMC - PubMed
    1. Bankovich, A. J., and K. C. Garcia. 2003. Not just any T cell receptor will do. Immunity 18:7-11. - PubMed
    1. Barouch, D. H., J. Kunstman, M. J. Kuroda, J. E. Schmitz, S. Santra, F. W. Peyerl, G. R. Krivulka, K. Beaudry, M. A. Lifton, D. A. Gorgone, D. C. Montefiori, M. G. Lewis, S. M. Wolinsky, and N. L. Letvin. 2002. Eventual AIDS vaccine failure in a rhesus monkey by viral escape from cytotoxic T lymphocytes. Nature 415:335-339. - PubMed

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