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A molecular switch in immunodominant HIV-1-specific CD8 T-cell epitopes shapes differential HLA-restricted escape

DOI: 10.1186/s12977-015-0149-5 DOI Help
PMID: 25808313 PMID Help

Authors: Henrik N Kløverpris (University of KwaZulu-Natal) , David Cole (Cardiff University) , Anna Fuller (Cardiff University) , Jonathan Carlson (Microsoft Research eScience Group, Los Angeles) , Konrad Beck (Cardiff University School of Dentistry) , Andrea Schauenburg (Cardiff University) , Pierre Rizkallah (Cardiff University) , Søren Buus (University of Copenhagen) , Andrew K Sewell (Cardiff University School of Medicine) , Philip Goulder (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Retrovirology , VOL 12

State: Published (Approved)
Published: February 2015
Diamond Proposal Number(s): 8096

Open Access Open Access

Abstract: Abstract: MHC anchor residue-modified “heteroclitic” peptides have been used in many cancer vaccine trials and often induce greater immune responses than the wild-type peptide. The best-studied system to date is the decamer MART-1/Melan-A26–35 peptide, EAAGIGILTV, where the natural alanine at position 2 has been modified to leucine to improve human leukocyte antigen (HLA)-A*0201 anchoring. The resulting ELAGIGILTV peptide has been used in many studies.We recently showed that T cells primed with the ELAGIGILTV peptide can fail to recognize the natural tumor-expressed peptide efficiently, thereby providing a potential molecular reason for why clinical trials of this peptide have been unsuccessful. Here, we solved the structure of a TCR in complex with HLA-A*0201-EAAGIGILTV peptide and compared it with its heteroclitic counterpart , HLA-A*0201-ELAGIGILTV. The data demonstrate that a suboptimal anchor residue at position 2 enables the TCR to “pull” the peptide away from the MHC binding groove, facilitating extra contacts with both the peptide and MHC surface. These data explain how a TCR can distinguish between two epitopes that differ by only a singleMHC anchor residue and demonstrate how weakMHC anchoring can enable an induced-fit interaction with the TCR. Our findings constitute a novel demonstration of the extreme sensitivity of the TCR to minor alterations in peptide conformation.

Subject Areas: Medicine, Biology and Bio-materials

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Other Facilities: No

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