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CD8+ T cell cross-reactivity profiles and HIV-1 immune escape towards an HLA-B35-restricted immunodominant Nef epitope

Motozono, Chihiro, Miles, John J., Hasan, Zafrul, Gatanaga, Hiroyuki, Meribe, Stanley C., Price, David ORCID:, Oka, Shinichi, Sewell, Andrew K. ORCID: and Ueno, Takamasa 2013. CD8+ T cell cross-reactivity profiles and HIV-1 immune escape towards an HLA-B35-restricted immunodominant Nef epitope. PLoS ONE 8 (6) , e66152. 10.1371/journal.pone.0066152

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Antigen cross-reactivity is an inbuilt feature of the T cell compartment. However, little is known about the flexibility of T cell recognition in the context of genetically variable pathogens such as HIV-1. In this study, we used a combinatorial library containing 24 billion octamer peptides to characterize the cross-reactivity profiles of CD8+ T cells specific for the immunodominant HIV-1 subtype B Nef epitope VY8 (VPLRPMTY) presented by HLA-B*35∶01. In conjunction, we examined naturally occurring antigenic variations within the VY8 epitope. Sequence analysis of plasma viral RNA isolated from 336 HIV-1-infected individuals revealed variability at position (P) 3 and P8 of VY8; Phe at P8, but not Val at P3, was identified as an HLA-B*35∶01-associated polymorphism. VY8-specific T cells generated from several different HIV-1-infected patients showed unique and clonotype-dependent cross-reactivity footprints. Nonetheless, all T cells recognized both the index Leu and mutant Val at P3 equally well. In contrast, competitive titration assays revealed that the Tyr to Phe substitution at P8 reduced T cell recognition by 50–130 fold despite intact peptide binding to HLA-B*35∶01. These findings explain the preferential selection of Phe at the C-terminus of VY8 in HLA-B*35∶01+ individuals and demonstrate that HIV-1 can exploit the limitations of T cell recognition in vivo.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: Q Science > QR Microbiology > QR180 Immunology
Publisher: Public Library of Science
ISSN: 1932-6203
Date of First Compliant Deposit: 1 April 2016
Last Modified: 05 May 2023 11:58

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