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Author Notes:

Correspondence: David K. Cole, coledk@cardiff.ac.uk; Andrew K. Sewell, sewellak@cardiff.ac.uk

David K. Cole, Anna Fuller, and Garry Dolton contributed equally to this work.

Author contributions: DC, AF, GD, EZ, ML, KM, JLB, FM, CH, AB, JSB, JM, AJAS, KB, BE, and PR performed and/or directed experiments, analysed data, and critiqued the manuscript.

DC and AKS conceived, funded, and directed the project and wrote the manuscript.

The authors would like to thank Diamond Light Source for beam time (proposals mx4532-1, mx6232-1, mx6232-9 and mx6232-10), and the staff of beamlines DLS I03, DLS I04-1 and DLS I24 for assistance with crystal testing and data collection.

We are extremely grateful to Andrew McMichael for providing advice and encouragement and to Anton van der Merwe for discussions about the biophysics and mechanism of SL9 TCR escape.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Subjects:

Research Funding:

This work was supported by the UK Biotechnology and Biological Sciences Research Council (Grant BB/H001085/1).

AKS is a Wellcome Trust Senior Investigator. FM was funded by a Tenovus PhD studentship.

DC is a Wellcome Trust Research Career Development Fellow (WT095767).

PR was supported by a RCUK Fellowship, and supported in part by grant GM067079 from the National Institute of General Medical Sciences, National Institutes of Health.

JM is an Australian National Health and Medical Research Council (NHMRC) Career Development Fellow (GNT1131732).

BDE was funded by NIH (R01 AI096879).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Immunology
  • T-cell
  • T-cell receptor
  • HIV
  • immune escape
  • MHC
  • T-CELL-RECEPTOR
  • HUMAN-IMMUNODEFICIENCY-VIRUS
  • PEPTIDE-MHC MULTIMERS
  • COMPLEX CLASS-I
  • LYMPHOCYTE RESPONSES
  • STRUCTURAL BASIS
  • CD8 CORECEPTOR
  • VACCINE DESIGN
  • ANTIGEN
  • BINDING

Dual Molecular Mechanisms Govern Escape at Immunodominant HLA A2-Restricted HIV Epitope

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Journal Title:

Frontiers in Immunology

Volume:

Volume 8

Publisher:

, Pages 1503-1503

Type of Work:

Article | Final Publisher PDF

Abstract:

Serial accumulation of mutations to fixation in the SLYNTVATL (SL9) immunodominant, HIV p17 Gag-derived, HLA A2-restricted cytotoxic T lymphocyte epitope produce the SLFNTIAVL triple mutant "ultimate" escape variant. These mutations in solvent-exposed residues are believed to interfere with TCR recognition, although confirmation has awaited structural verification. Here, we solved a TCR co-complex structure with SL9 and the triple escape mutant to determine the mechanism of immune escape in this eminent system. We show that, in contrast to prevailing hypotheses, the main TCR contact residue is 4N and the dominant mechanism of escape is not via lack of TCR engagement. Instead, mutation of solvent-exposed residues in the peptide destabilise the peptide-HLA and reduce peptide density at the cell surface. These results highlight the extraordinary lengths that HIV employs to evade detection by high-affinity TCRs with a broad peptide-binding footprint and necessitate re-evaluation of this exemplar model of HIV TCR escape.

Copyright information:

© 2017 Cole, Fuller, Dolton, Zervoudi, Legut, Miles, Blanchfield, Madura, Ho lland, Bulek, Bridgeman, Miles, Schauenburg, Beck, Evavold, Rizkallah and Sewell.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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