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

Cole DK, Fuller A, Dolton G, Zervoudi E, Legut M, Miles K, Blanchfield L, Madura F, Holland CJ, Bulek AM, Bridgeman JS, Miles JJ, Schauenburg AJA, Beck K, Evavold BD, Rizkallah PJ, Sewell AK
Front Immunol 8 1503 (2017)
Related entries: 5nmd, 5nme, 5nmf, 5nmg, 5nmh

Cited: 17 times
EuropePMC logo PMID: 29209312

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.

Articles - 5nmk mentioned but not cited (1)

  1. Dual Molecular Mechanisms Govern Escape at Immunodominant HLA A2-Restricted HIV Epitope. Cole DK, Fuller A, Dolton G, Zervoudi E, Legut M, Miles K, Blanchfield L, Madura F, Holland CJ, Bulek AM, Bridgeman JS, Miles JJ, Schauenburg AJA, Beck K, Evavold BD, Rizkallah PJ, Sewell AK. Front Immunol 8 1503 (2017)


Reviews citing this publication (1)

  1. TCR Recognition of Peptide-MHC-I: Rule Makers and Breakers. Szeto C, Lobos CA, Nguyen AT, Gras S. Int J Mol Sci 22 (2020)

Articles citing this publication (15)

  1. Emergence of immune escape at dominant SARS-CoV-2 killer T cell epitope. Dolton G, Rius C, Hasan MS, Wall A, Szomolay B, Behiry E, Whalley T, Southgate J, Fuller A, COVID-19 Genomics UK (COG-UK) consortium, Morin T, Topley K, Tan LR, Goulder PJR, Spiller OB, Rizkallah PJ, Jones LC, Connor TR, Sewell AK. Cell 185 2936-2951.e19 (2022)
  2. Allosteric activation of T cell antigen receptor signaling by quaternary structure relaxation. Lanz AL, Masi G, Porciello N, Cohnen A, Cipria D, Prakaash D, Bálint Š, Raggiaschi R, Galgano D, Cole DK, Lepore M, Dushek O, Dustin ML, Sansom MSP, Kalli AC, Acuto O. Cell Rep 36 109375 (2021)
  3. Optimized Peptide-MHC Multimer Protocols for Detection and Isolation of Autoimmune T-Cells. Dolton G, Zervoudi E, Rius C, Wall A, Thomas HL, Fuller A, Yeo L, Legut M, Wheeler S, Attaf M, Chudakov DM, Choy E, Peakman M, Sewell AK. Front Immunol 9 1378 (2018)
  4. Peptide cargo tunes a network of correlated motions in human leucocyte antigens. Hopkins JR, Crean RM, Catici DAM, Sewell AK, Arcus VL, Van der Kamp MW, Cole DK, Pudney CR. FEBS J 287 3777-3793 (2020)
  5. ADAM17-dependent proteolysis of L-selectin promotes early clonal expansion of cytotoxic T cells. Mohammed RN, Wehenkel SC, Galkina EV, Yates EK, Preece G, Newman A, Watson HA, Ohme J, Bridgeman JS, Durairaj RRP, Moon OR, Ladell K, Miners KL, Dolton G, Troeberg L, Kashiwagi M, Murphy G, Nagase H, Price DA, Matthews RJ, Knäuper V, Ager A. Sci Rep 9 5487 (2019)
  6. Molecular Basis of a Dominant SARS-CoV-2 Spike-Derived Epitope Presented by HLA-A*02:01 Recognised by a Public TCR. Szeto C, Nguyen AT, Lobos CA, Chatzileontiadou DSM, Jayasinghe D, Grant EJ, Riboldi-Tunnicliffe A, Smith C, Gras S. Cells 10 2646 (2021)
  7. T cell receptor interactions with human leukocyte antigen govern indirect peptide selectivity for the cancer testis antigen MAGE-A4. Coles CH, McMurran C, Lloyd A, Hock M, Hibbert L, Raman MCC, Hayes C, Lupardus P, Cole DK, Harper S. J Biol Chem 295 11486-11494 (2020)
  8. TCRmodel: high resolution modeling of T cell receptors from sequence. Gowthaman R, Pierce BG. Nucleic Acids Res. 46 W396-W401 (2018)
  9. Association of human leukocyte antigen alleles and supertypes with immunogenicity of oral rotavirus vaccine given to infants in China. Liu Y, Guo T, Yu Q, Zhang H, Du J, Zhang Y, Xia S, Yang H, Li Q. Medicine (Baltimore) 97 e12706 (2018)
  10. Characterization of amino acid residues of T-cell receptors interacting with HLA-A*02-restricted antigen peptides. Zhu Y, Huang C, Su M, Ge Z, Gao L, Shi Y, Wang X, Chen J. Ann Transl Med 9 495 (2021)
  11. Functional Profile of CD8+ T-Cells in Response to HLA-A*02:01-Restricted Mutated Epitopes Derived from the Gag Protein of Circulating HIV-1 Strains from Medellín, Colombia. Sánchez-Martínez A, Acevedo-Sáenz L, Alzate-Ángel JC, Álvarez CM, Guzmán F, Roman T, Urcuqui-Inchima S, Cardona-Maya WD, Velilla PA. Front Immunol 13 793982 (2022)
  12. GPU-Accelerated Discovery of Pathogen-Derived Molecular Mimics of a T-Cell Insulin Epitope. Whalley T, Dolton G, Brown PE, Wall A, Wooldridge L, van den Berg H, Fuller A, Hopkins JR, Crowther MD, Attaf M, Knight RR, Cole DK, Peakman M, Sewell AK, Szomolay B. Front Immunol 11 296 (2020)
  13. Nonstimulatory peptide-MHC enhances human T-cell antigen-specific responses by amplifying proximal TCR signaling. Zhao X, Sankaran S, Yap J, Too CT, Ho ZZ, Dolton G, Legut M, Ren EC, Sewell AK, Bertoletti A, MacAry PA, Brzostek J, Gascoigne NRJ. Nat Commun 9 2716 (2018)
  14. SARS-CoV-2 infection establishes a stable and age-independent CD8+ T cell response against a dominant nucleocapsid epitope using restricted T cell receptors. Choy C, Chen J, Li J, Gallagher DT, Lu J, Wu D, Zou A, Hemani H, Baptiste BA, Wichmann E, Yang Q, Ciffelo J, Yin R, McKelvy J, Melvin D, Wallace T, Dunn C, Nguyen C, Chia CW, Fan J, Ruffolo J, Zukley L, Shi G, Amano T, An Y, Meirelles O, Wu WW, Chou CK, Shen RF, Willis RA, Ko MSH, Liu YT, De S, Pierce BG, Ferrucci L, Egan J, Mariuzza R, Weng NP. Nat Commun 14 6725 (2023)
  15. Unsupervised and supervised AI on molecular dynamics simulations reveals complex characteristics of HLA-A2-peptide immunogenicity. Weber JK, Morrone JA, Kang SG, Zhang L, Lang L, Chowell D, Krishna C, Huynh T, Parthasarathy P, Luan B, Alban TJ, Cornell WD, Chan TA. Brief Bioinform 25 bbad504 (2023)


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