CD8+ T Cell Cross-Reactivity Profiles and HIV-1 Immune Escape towards an HLA-B35-Restricted Immunodominant Nef Epitope

Chihiro Motozono, John J. Miles, Zafrul Hasan, Hiroyuki Gatanaga, Stanley C. Meribe, David A. Price, Shinichi Oka, Andrew K. Sewell, Takamasa Ueno

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)


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.

Original languageEnglish
Article numbere66152
JournalPloS one
Issue number6
Publication statusPublished - Jun 17 2013
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Biochemistry,Genetics and Molecular Biology
  • General Agricultural and Biological Sciences
  • General


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