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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., Ho, Bosco K., McVicar, Daniel W., Brooks, Andrew G., Purcell, Anthony W., Rossjohn, Jamie 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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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: 24 Nov 2020 17:52

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