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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 Ramarathinam, Sri O'Connor, Geraldine M. Hughes, Victoria A. Hitchen, Corinne Price, David A. Ho, Bosco McVicar, Daniel W. Brooks, Andrew G.
Pymm, Phillip
Illing, Patricia
Ramarathinam, Sri
O'Connor, Geraldine M.
Hughes, Victoria A.
Hitchen, Corinne
Price, David A.
Ho, Bosco
McVicar, Daniel W.
Brooks, Andrew G.
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Other Contributors
EPub Date
Publication Date
2017-02-20
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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.
Citation
Pymm, P., Illing, P. T., Ramarathinam, S. H., O'Connor, G. M., Hughes, V. A., Hitchen, C.,... Vivian, J. P. (2017). MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape. Nature Structural & Molecular Biology, 24, 387-394.
Publisher
Nature Research
Journal
Nature Structural & Molecular Biology
Research Unit
DOI
10.1038/nsmb.3381
PubMed ID
PubMed Central ID
Type
Article
Language
en
Description
This document is the Accepted Manuscript version of a published work that appeared in final form in Nature Structural & Molecular Biology. To access the final edited and published work see http://dx.doi.org/10.1038/nsmb.3381.
Series/Report no.
ISSN
1545-9993
EISSN
1545-9985