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

Nature Medicine volume 14, pages 1390–1395 (2008)Cite this article

Abstract

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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Figure 1: SL9-specific cell staining with high-affinity TCR.
Figure 2: CD8 T cells expressing supraphysiologic SL9-specific TCRs show an increased frequency of polyfunctional cells and an increased ability to control HIV-1 spread.
Figure 3: High-affinity TCR-transduced CD8 T cells can effectively recognize SL9 escape mutant peptides and suppress infection by SL9 escape HIV-1 variants.

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Acknowledgements

We are grateful to R. Ashfield, B. Classon and R. Vonderheide for their help in initiating collaborations. We thank P. Goulder, A. Leslie and T. Scriba for encouragement, critical reading of the manuscript and helpful suggestions. A. Bennett designed the TCR expression constructs. M. Milone confirmed the SL9 sequence of 92BR-017, 92BR-018 and 92BR-028. A.K.S. was a Wellcome Trust Senior Fellow and is funded by Cardiff University. This work was also supported in part by US National Institutes of Health grants R21 AI060477, R01 CA105216 and PO1 AI066290. The authors would like to dedicate this study to the memory of our colleague and friend Jonathan Michael Boulter, who contributed immensely in the field of soluble T cell receptors.

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Author notes

  1. Andrew K Sewell and James L Riley: These authors contributed equally to this work.

Authors and Affiliations

  1. Abramson Family Cancer Research Institute and Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 556 BRB II/III, 421 Curie Boulevard, Philadelphia, 19104-6160, Pennsylvania, USA

    Angel Varela-Rohena, Megan M Suhoski, Richard G Carroll, Carl H June & James L Riley

  2. Immunocore Ltd., 57c Milton Park, Abingdon, OX14 4RX, Oxon, UK

    Peter E Molloy, Steven M Dunn, Yi Li, Tara Mahon, Deborah H Sutton, Ruth Moysey, Brian J Cameron, Annelise Vuidepot & Marco A Purbhoo

  3. The Peter Medawar Building for Pathogen Research, University of Oxford, South Parks Road, Oxford, OX1 3SY, UK

    Anita Milicic, Bruno Laugel, Rodney E Phillips & Andrew K Sewell

  4. Department of Medical Biochemistry and Immunology, Henry Wellcome Building, Cardiff University School of Medicine, Heath Park, CF14 4XN, Cardiff, UK

    David K Cole & Andrew K Sewell

  5. Adaptimmune Ltd., 57c Milton Park, Abingdon, OX14 4RX, Oxon, UK

    Bent K Jakobsen

Authors
  1. Angel Varela-Rohena
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Contributions

A.V.-R., M.M.S. and R.G.C. performed the TCR gene transfer experiments in the laboratories of C.H.J. and J.L.R. P.E.M., S.M.D. and Y.L. undertook the phage display selection. B.J.C., S.M.D. and R.M. made the MHC and TCR proteins. A.V., T.M. and D.K.C. performed the surface plasmon resonance. D.H.S. and M.A.P. performed the microscopic analyses. A.M. and B.L. undertook the experiments with primary T cells grown by A.K.S. R.E.P. secured the clinical materials. B.K.J., A.K.S. and J.L.R. conceived and wrote the study.

Corresponding authors

Correspondence to Bent K Jakobsen or James L Riley.

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Supplementary Figures 1–6, Supplementary Tables 1–2 and Supplementary Methods (PDF 3368 kb)

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Varela-Rohena, A., Molloy, P., Dunn, S. et al. Control of HIV-1 immune escape by CD8 T cells expressing enhanced T-cell receptor. Nat Med 14, 1390–1395 (2008). https://doi.org/10.1038/nm.1779

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