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

Cole, David K., 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, Evavold, Brian D., Rizkallah, Pierre J., and Sewell, Andrew K. (2017) Dual molecular mechanisms govern escape at immunodominant HLA A2-restricted HIV epitope. Frontiers in Immunology, 8. 1503.

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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.

Item ID: 51689
Item Type: Article (Research - C1)
ISSN: 1664-3224
Keywords: T-cell, T-cell receptor, HIV, immune escape, MHC
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© 2017 Cole, Fuller, Dolton, Zervoudi, Legut, Miles, Blanchfield, Madura, Holland, Bulek, Bridgeman, Miles, Schauenburg, Beck, Evavold, Rizkallah and Sewell. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Date Deposited: 29 Nov 2017 07:45
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3204 Immunology > 320402 Applied immunology (incl. antibody engineering, xenotransplantation and t-cell therapies) @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 100%
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