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HIV's considerable capacity to vary its HLA-I-restricted peptide antigens allows it to escape from host cytotoxic T lymphocytes (CTLs). Nevertheless, therapeutics able to target HLA-I-associated antigens, with specificity for the spectrum of preferred CTL escape mutants, could prove effective. Here we use phage display to isolate and enhance a T-cell antigen receptor (TCR) originating from a CTL line derived from an infected person and specific for the immunodominant HLA-A(*)02-restricted, HIVgag-specific peptide SLYNTVATL (SL9). High-affinity (K(D) < 400 pM) TCRs were produced that bound with a half-life in excess of 2.5 h, retained specificity, targeted HIV-infected cells and recognized all common escape variants of this epitope. CD8 T cells transduced with this supraphysiologic TCR produced a greater range of soluble factors and more interleukin-2 than those transduced with natural SL9-specific TCR, and they effectively controlled wild-type and mutant strains of HIV at effector-to-target ratios that could be achieved by T-cell therapy.

Original publication

DOI

10.1038/nm.1779

Type

Journal article

Journal

Nat Med

Publication Date

12/2008

Volume

14

Pages

1390 - 1395

Keywords

Amino Acid Sequence, CD8-Positive T-Lymphocytes, Cells, Cultured, Gene Products, gag, HIV-1, Humans, Mutation, Peptide Fragments, Protein Binding, Receptors, Antigen, T-Cell, Solubility