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Dual molecular mechanisms govern escape at immunodominant HLA A2-restricted HIV epitope
Authors:
David K.
Cole
(Cardiff University School of Medicine)
,
Anna
Fuller
(Cardiff University School of Medicine)
,
Garry
Dolton
(Cardiff University School of Medicine)
,
Efthalia
Zervoudi
(Cardiff University School of Medicine)
,
Mateusz
Legut
(Cardiff University School of Medicine)
,
Kim
Miles
(Cardiff University School of Medicine)
,
Lori
Blanchfield
(Emory University)
,
Florian
Madura
(Cardiff University School of Medicine)
,
Christopher J.
Holland
(Cardiff University School of Medicine)
,
Anna M.
Bulek
(Cardiff University School of Medicine)
,
John S.
Bridgeman
(Cardiff University School of Medicine)
,
John J.
Miles
(Cardiff University School of Medicine; James Cook University)
,
Andrea J. A.
Schauenburg
(James Cook University)
,
Konrad
Beck
(Cardiff University School of Dentistry)
,
Brian D.
Evavold
(Emory University)
,
Pierre
Rizkallah
(Cardiff University School of Medicine)
,
Andrew K.
Sewell
(Cardiff University School of Medicine)
Co-authored by industrial partner:
No
Type:
Journal Paper
Journal:
Frontiers In Immunology
, VOL 8
State:
Published (Approved)
Published:
November 2017
Diamond Proposal Number(s):
4532
,
6232
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.
Journal Keywords: T-cell; T-cell receptor; HIV; immune escape; MHC
Diamond Keywords: Human Immunodeficiency Virus (HIV); Viruses
Subject Areas:
Biology and Bio-materials
Instruments:
I03-Macromolecular Crystallography
,
I04-1-Macromolecular Crystallography (fixed wavelength)
,
I24-Microfocus Macromolecular Crystallography
Added On:
16/11/2017 10:31
Discipline Tags:
Pathogens
Infectious Diseases
Health & Wellbeing
Structural biology
Biophysics
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)