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MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape

Abstract

Major histocompatibility complex class I (MHC-I) molecules play a crucial role in immunity by capturing peptides for presentation to T cells and natural killer (NK) cells. The peptide termini are tethered within the MHC-I antigen-binding groove, but it is unknown whether other presentation modes occur. Here we show that 20% of the HLA-B*57:01 peptide repertoire comprises N-terminally extended sets characterized by a common motif at position 1 (P1) to P2. Structures of HLA-B*57:01 presenting N-terminally extended peptides, including the immunodominant HIV-1 Gag epitope TW10 (TSTLQEQIGW), showed that the N terminus protrudes from the peptide-binding groove. The common escape mutant TSNLQEQIGW bound HLA-B*57:01 canonically, adopting a dramatically different conformation than the TW10 peptide. This affected recognition by killer cell immunoglobulin-like receptor (KIR) 3DL1 expressed on NK cells. We thus define a previously uncharacterized feature of the human leukocyte antigen class I (HLA-I) immunopeptidome that has implications for viral immune escape. We further suggest that recognition of the HLA-B*57:01-TW10 epitope is governed by a 'molecular tension' between the adaptive and innate immune systems.

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Figure 1: HLA-B*57:01 in complex with the TW10 peptide.
Figure 2: Characterization of N-terminally extended peptides.
Figure 3: The HIV-1 Gag repertoire of HLA-B*57:01.
Figure 4: Cartoon representations of the crystal structure of HLA-B*57:01 (light gray) in complex with the TSTFEDVKILAF peptide (cyan).
Figure 5: Comparison of the HLA-B*57:01–TW10 and HLA-B*57:01–T3N ternary complex structures with KIR3DL1*001.
Figure 6: HLA-B*57:01 TW10 and T3N binding to KIR3DL1.

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Acknowledgements

This work was supported by project grants from the National Health and Medical Research Council of Australia (NH&MRC; APP1063829 to A.W.P., and APP1099814 to J.P.V. and D.A.P.) and the Australian Research Council (ARC; DP150104503 to J.R. and A.W.P.). A.W.P. is an NH&MRC Senior Research Fellow. P.T.I. is an NH&MRC Early Career Fellow. S.H.R. is the recipient of an Australian Postgraduate Award. D.A.P. is supported by a Wellcome Trust Senior Investigator Award. J.R. is supported by an ARC Laureate Fellowship. This work was funded in part by the intramural program of the National Institutes of Health, National Cancer Institute. This research was carried out in part on the MX2 beamline at the Australian Synchrotron, Victoria, Australia. J. Mak (Deakin University, Melbourne, Victoria, Australia) provided the Gag plasmid and generated the antibody used to assay Gag expression in transfectants.

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Contributions

P.P., P.T.I., S.H.R. and G.M.O'C. collected and analyzed the data and wrote the manuscript with guidance and intellectual input from D.W.M., A.G.B., A.W.P., J.R. and J.P.V. B.K.H. assisted with bioinformatics analysis. V.A.H. assisted with hydrogen deuterium assays. C.H. assisted with cell culture and protein purification. D.A.P. and all other authors contributed to intellectual discussions on the manuscript.

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Correspondence to Anthony W Purcell, Jamie Rossjohn or Julian P Vivian.

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Integrated supplementary information

Supplementary Figure 1 Hydrogen-deuterium exchange spectra for the TW10 peptide in complex with HLA-B*57:01 and free in solution.

(a) Peptide in complex with HLA-B*57:01 at 0 seconds showing the normal isotopic distribution for a singly charged peptide (b) The peptide in complex with HLA-B*57:01 after 10 seconds incubation in D2O showing a single Gaussian distribution indicative of a single bound conformation and (c) the peptide free in a solution of D2O for 10 seconds showing a bimodal distribution suggesting multiple conformations in solution. Spectra displayed are from a single experiment and represent data from three independent experiments.

Supplementary Figure 2 Circular dichroism readings taken at 222 nm over a temperature range of 20–90 °C for the HLA-B*57:01–TW10 complex (a) and the HLA-B*57:01-T3N complex (b).

Tm was calculated by fitting a sigmoidal dose-response curve and taking the IC50 value of the curve. Data represent a single experiment.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–2 and Supplementary Note 1 (PDF 1206 kb)

Supplementary Table 1

Combined HLA-B*57:01 data set (XLSX 943 kb)

Supplementary Table 2

Alignment of N-terminally extended peptide sets (XLSX 441 kb)

Supplementary Table 3

Extended sets containing C-terminal or N- and C-terminal extensions (XLSX 47 kb)

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Pymm, P., Illing, P., Ramarathinam, S. et al. MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape. Nat Struct Mol Biol 24, 387–394 (2017). https://doi.org/10.1038/nsmb.3381

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