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Strong TCR Conservation and Altered T Cell Cross-Reactivity Characterize a B*57-Restricted Immune Response in HIV-1 Infection^1,2

Geraldine M. A. Gillespie^3,4,*, Guillaume Stewart-Jones^4,, Jaya Rengasamy^*, Tara Beattie^*, Job. J. Bwayo, Francis A. Plummer, Rupert Kaul^¶, Andrew J. McMichael^*, Philippa Easterbrook^||, Tao Dong^*, E. Yvonne Jones and Sarah L. Rowland-Jones^*

^* Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, United Kingdom; Division of Structural Biology, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, United Kingdom; Department of Medical Microbiology, University of Nairobi, Nairobi, Kenya; Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada; ^¶ Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; and ^|| Academic Department of HIV/GUM, Guy’s, King’s, and St. Thomas’ School of Medicine, Weston Education Centre, London, United Kingdom

HLA-B*57 is associated with slower disease progression to AIDS, and CD8⁺ T cell responses to B*57-restricted epitopes are thought to contribute to this protective effect. In this study, we evaluate the B*57-restricted p24 KAFSPEVIPMF (KF11) immune response which is immunodominant during chronic infection. Previously, we observed that the KF11 clade variants KGFNPEVIPMF [A2G,S4N] and KAFNPEIIMPF [S4N,V7I], sharing a position 4 mutation, are differentially recognized by KF11-specific T cells. By combining structural and cellular studies, we now demonstrate that the KF11 and [A2G,S4N] epitopes induce distinct functional responses in [A2G,S4N] and KF11-specific T cells, respectively, despite minimal structural differences between the individual B*57-peptide complexes. Recently, we also elucidated the highly distinct structure of KF11 in complex with B*5703, and have now characterized the CD8⁺ T cell repertoire recognizing this epitope. We now report striking features of TCR conservation both in terms of TCR V and V chain usage, and throughout the hypervariable region. Collectively, our findings highlight unusual features of the B*5701/B*5703-KF11-specific immune responses which could influence disease progression and that might be important to consider when designing future vaccine regimens.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Elizabeth Glaser Pediatric AIDS Foundation Grant No. 77474-28-PF, and funding from the Medical Research Council, Wellcome Trust, and Cancer Research U.K.

² Atomic coordinates and structure factor amplitudes for the HLA-B*5703-A2G,S4N and the HLA-B*5703-S4N,V7I complexes have been deposited in the Protein Data Bank under accession codes 2HJK and 2HJL, respectively.

³ Address correspondence and reprint requests to Dr. Geraldine M. A. Gillespie, Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9DS, U.K. E-mail address: ggillesp{at}hammer.imm.ox.ac.uk

⁴ G.M.A.G. and G.S.-J. contributed equally to this study.

⁵ Abbreviations used in this paper: BCL, autologous B cell; SFU, spot-forming unit; h, human; ICS, intracellular cytokine staining; FSC, forward scatter; SSC, side scatter.

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