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

Cole, David K. ORCID:, Fuller, Anna, Dolton, Garry, Zervoudi, Efthalia, Legut, Mateusz, Miles, Kim, Blanchfield, Lori, Madura, Florian, Holland, Christopher J., Bulek, Anna M., Bridgeman, John S., Miles, John J., Schauenburg, Andrea J. A., Beck, Konrad ORCID:, Evavold, Brian D., Rizkallah, Pierre J. ORCID: and Sewell, Andrew K. ORCID: 2017. Dual molecular mechanisms govern escape at immunodominant HLA A2-restricted HIV epitope. Frontiers in Immunology 8 , 1503. 10.3389/fimmu.2017.01503

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Serial accumulation of mutations to fixation in the SLYNTVATL (SL9) immunodominant, HIV p17 Gag-derived, HLA A2-restricted CTL 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 destabilize 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 reevaluation of this exemplar model of HIV TCR escape.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Dentistry
Subjects: R Medicine > R Medicine (General)
Additional Information: This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).
Publisher: Frontiers Media
ISSN: 1664-3224
Funders: Wellcome Trust
Date of First Compliant Deposit: 26 October 2017
Date of Acceptance: 25 October 2017
Last Modified: 05 Jan 2024 08:11

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