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

P Pymm; PT Illing; SH Ramarathinam; GM O'Connor; VA Hughes; C Hitchen; DA Price; BK Ho; DW McVicar; AG Brooks; AW Purcell; J Rossjohn; JP Vivian

Journal article

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

P Pymm, PT Illing, SH Ramarathinam, GM O'Connor, VA Hughes, C Hitchen, DA Price, BK Ho, DW McVicar, AG Brooks, AW Purcell, J Rossjohn, JP Vivian

Nature Structural and Molecular Biology | NATURE PUBLISHING GROUP | Published : 2017

DOI: 10.1038/nsmb.3381

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 ..

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University of Melbourne Researchers

Phillip Pymm Author

Andrew Brooks Author

Jamie Rossjohn Author

Julian Vivian Author

Grants

Awarded by National Institutes of Health

Funding 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.