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

Phillip Pymm, Patricia T Illing, Sri H Ramarathinam, Geraldine M. O'Connor, Victoria A Hughes, Corinne Hitchen, David A Price, Bosco K Ho, Daniel W McVicar, Andrew G Brooks, Anthony W Purcell, Jamie Rossjohn, Julian P Vivian

Research output: Contribution to journalArticleResearchpeer-review

28 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)387-394
Number of pages8
JournalNature Structural and Molecular Biology
Volume24
Issue number4
DOIs
Publication statusPublished - Apr 2017

Keywords

  • immunology
  • x-ray crystallography

Cite this

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 ; Vivian, Julian P. / MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape. In: Nature Structural and Molecular Biology. 2017 ; Vol. 24, No. 4. pp. 387-394.
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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; Vivian, Julian P.

In: Nature Structural and Molecular Biology, Vol. 24, No. 4, 04.2017, p. 387-394.

Research output: Contribution to journalArticleResearchpeer-review

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