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Dual molecular mechanisms govern escape at immunodominant HLA A2-restricted HIV epitope

DOI: 10.3389/fimmu.2017.01503 DOI Help

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)