Fine-tuning of T-cell receptor avidity to increase HIV epitope variant recognition by cytotoxic T lymphocytes

Michael S. Bennett, Aviva Joseph, Hwee L. Ng, Harris Goldstein, Otto O. Yang

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Objective: T-cell receptor (TCR) gene therapy is an approach being considered for HIV-1, but epitope mutation is a significant barrier. We assessed whether HIV-specific TCR can be modified to have broader coverage of epitope variants by recombining polymorphisms between public clonotype TCR sequences. Design: Public clonotype TCRs recognizing the same epitope often differ by polymorphisms in their third complementarity determining regions (CDR3). We assessed whether novel combinations of such polymorphisms could improve TCR recognition of epitope variation. Methods: A TCR recognizing the HLA A*0201-restricted epitope SLYNTVATL (Gag 77-85, SL9) was engineered to have combinations of four polymorphisms in the CDR3 regions compared to another SL9-specific TCR. These novel TCRs were screened for functional avidities against SL9 epitope variants and abilities to mediate cytotoxic T-lymphocyte suppression of HIV-1 containing the same epitope variants. Results: The TCRs varied modestly in functional avidities for SL9 variants, due to alterations in affinity. This translated to differences in antiviral activities against HIV-1 when functional avidity changes crossed the previously defined threshold required for efficient recognition of HIV-1-infected cells. Higher avidity TCR mutants had generally broader recognition of SL9 variants. Conclusion: These results indicate that rationally targeted increases in functional avidities can be utilized to maximize the antiviral breadth of transgenic TCRs. In contrast to previously reported random mutagenesis to markedly increase functional avidities, tuning through recombining naturally occurring polymorphisms may offer a more physiologic approach that minimizes the risk of deleterious TCR reactivities.

Original languageEnglish (US)
Pages (from-to)2619-2628
Number of pages10
JournalAIDS
Volume24
Issue number17
DOIs
StatePublished - Nov 13 2010
Externally publishedYes

Keywords

  • HIV
  • T-cell receptor
  • cytotoxic T lymphocytes
  • gene therapy
  • immune evasion

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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