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

Pymm, Phillip, Illing, Patricia T., Ramarathinam, Sri H., O'Connor, Geraldine M., Hughes, Victoria A., Hitchen, Corinne, Price, David A. ORCID: https://orcid.org/0000-0001-9416-2737, Ho, Bosco K., McVicar, Daniel W., Brooks, Andrew G., Purcell, Anthony W., Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522 and Vivian, Julian P. 2017. MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape. Nature Structural and Molecular Biology 24 , pp. 387-394. 10.1038/nsmb.3381

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Publisher:	Nature Publishing Group
ISSN:	1545-9993
Date of First Compliant Deposit:	2 June 2017
Date of Acceptance:	20 January 2017
Last Modified:	20 Nov 2024 01:30
URI:	https://orca.cardiff.ac.uk/id/eprint/101075

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