HLA-E–restricted T cells primed by a modified HLA-B*57:01–restricted HIV-1 peptide suppress HIV-1 replication
Hong Sun, Hongbing Yang, Max N. Quastel, Simon Brackenridge, Wanlin He, Anna E. Kliszczak, Margarida Rei, Persephone Borrow, Geraldine M. Gillespie, Andrew J. McMichael
Hong Sun, Hongbing Yang, Max N. Quastel, Simon Brackenridge, Wanlin He, Anna E. Kliszczak, Margarida Rei, Persephone Borrow, Geraldine M. Gillespie, Andrew J. McMichael
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Research Article AIDS/HIV Immunology

HLA-E–restricted T cells primed by a modified HLA-B*57:01–restricted HIV-1 peptide suppress HIV-1 replication

Abstract

HLA-E–restricted HIV-specific T cells offer exciting possibilities for immunotherapy. However, HLA-E binding peptides are rare. A recent study showed that in HLA-B*57:01–positive people with HIV, the peptide that dominates the T cell response, KAFSPEVIPMF (KF11), also stimulates HLA-E–restricted T cells, even though direct binding of this peptide to HLA-E could not be demonstrated. We therefore changed position 2 alanine for methionine in the peptide (referred to as KMF11), which greatly enhanced binding to HLA-E. This enabled the generation of stabilized HLA-E-KMF11 tetramers, which were used to select and then grow specific T cell clones from T cells of HLA-B*57:01–negative blood donors primed with this peptide in vitro. Approximately 20% of these T cell clones reacted with HLA-E–positive cells presenting the native KF11 peptide. Furthermore, these T cells inhibited replication of HIV-1 NL4-3 in CD4+ T cells in vitro. Therefore, this native peptide can be presented by HLA-E to CD8+ T cells, although priming in vivo may depend on cross-reactivities to classical MHC-Ia types. Nevertheless, such T cells could be exploitable for immunotherapy given the conservation of this HIV-1 peptide epitope and the non-polymorphism in HLA-E.

Authors

Hong Sun, Hongbing Yang, Max N. Quastel, Simon Brackenridge, Wanlin He, Anna E. Kliszczak, Margarida Rei, Persephone Borrow, Geraldine M. Gillespie, Andrew J. McMichael

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Figure 5

Antiviral effect of KMF11-specific TCR CD8+ T cell transductants against HIV-infected primary CD4+ T cells in a viral suppression assay.

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Antiviral effect of KMF11-specific TCR CD8+ T cell transductants against...
(A) KMF11-specific TCRs (C02, C10, C26, C27) and an irrelevant HLA-E–restricted TCR specific for a SARS-CoV-2–derived peptide were transduced into primary CD8+ T cells and then stained with anti-mouse Cβ antibody, anti-CD8/CD3, and Live/Dead Fixable Aqua Dead Cell Stain kit. Percentages of mTCR+ cells are indicated. Postenrichment staining of mTCR+CD8+ T cell transductants for each TCR is shown. Untransduced CD8+ T cells were included as controls. (B) CD8+ T cell transductants were cocultured with HIV-infected primary CD4+ T cells at E/T ratios of 1:1 and 5:1 for 5 days. Intracellular HIV Gag staining (KC57-FITC) was performed after surface staining with anti-CD8/CD3/CD4 and Live/Dead Fixable Aqua Dead Cell Stain kit. The percentages of HIV Gag expression in HIV-infected primary CD3+CD8– T cells were assessed. Uninfected CD4+ T cells and HIV-infected CD4+ T cells without effectors were included as negative and positive controls, respectively. (C) The suppressive effect of KMF11-specific TCR transductants against HIV-infected CD4+ T cells was assessed at E/T ratios of 1:1 and 5:1. Data are represented as median with 95% CI from 2 independent experiments (n = 4 donors). Statistical significance between KMF11 TCR transductants and irrelevant TCR controls was determined using the Mann-Whitney U test (*P < 0.05). (D) Suppression of HIV-infected CD4+ T cells by HLA-B*57:01–restricted TCR transductants (AGA1) was evaluated at E/T ratios of 1:1 and 5:1. Data are shown as mean ± SEM from 2 independent experiments. CD4+ T cell targets were derived from 6 donors, comprising 3 HLA-B*57:01–positive and 3 HLA-B*57:01–negative individuals. Each donor is represented by a distinct colored circle. Statistical comparisons between AGA1 TCR transductants and irrelevant TCR controls were performed using a 2-tailed paired t test.