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Publication Abstract from PubMed

Cytotoxic-T-lymphocyte (CTL) mediated control of HIV-1 is enhanced by targeting highly networked epitopes in complex with human-leukocyte-antigen-class-I (HLA-I). However, the extent to which the presenting HLA allele contributes to this process is unknown. Here we examine the CTL response to QW9, a highly networked epitope presented by the disease-protective HLA-B57 and disease-neutral HLA-B53. Despite robust targeting of QW9 in persons expressing either allele, T cell receptor (TCR) cross-recognition of the naturally occurring variant QW9_S3T is consistently reduced when presented by HLA-B53 but not by HLA-B57. Crystal structures show substantial conformational changes from QW9-HLA to QW9_S3T-HLA by both alleles. The TCR-QW9-B53 ternary complex structure manifests how the QW9-B53 can elicit effective CTLs and suggests sterically hindered cross-recognition by QW9_S3T-B53. We observe populations of cross-reactive TCRs for B57, but not B53 and also find greater peptide-HLA stability for B57 in comparison to B53. These data demonstrate differential impacts of HLAs on TCR cross-recognition and antigen presentation of a naturally arising variant, with important implications for vaccine design.

Molecular basis of differential HLA class I-restricted T cell recognition of a highly networked HIV peptide.,Li X, Singh NK, Collins DR, Ng R, Zhang A, Lamothe-Molina PA, Shahinian P, Xu S, Tan K, Piechocka-Trocha A, Urbach JM, Weber JK, Gaiha GD, Takou Mbah OC, Huynh T, Cheever S, Chen J, Birnbaum M, Zhou R, Walker BD, Wang JH Nat Commun. 2023 May 22;14(1):2929. doi: 10.1038/s41467-023-38573-8. PMID:37217466^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.