Control of HIV-1 immune escape by CD8 T cells expressing enhanced T-cell receptor

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Abstract
In HIV research, new types of reagents are needed to target infected cells and overcome HIV's ability to vary its HLA-I-restricted antigens and escape from host cytotoxic T lymphocytes. Here Varela-Rohena and colleagues use phage display technology to generate high-affinity T-cell antigen receptors that recognize common epitope-escape variants of the immunodominant HLA-A*02-restricted, HIVgag-specific peptide SLYNTVATL (SL9). 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 (KD < 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.

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