Key Points

A pair of public TCRs was identified from White and Japanese patients with HIV.

The public TCRs can recognize both wild-type and Y2F-mutated Nef138-8 epitopes.

Public TCRs binding to pHLA mostly rely on the interaction between TCR and HLA.

Abstract

Cross-recognized public TCRs against HIV epitopes have been proposed to be important for the control of AIDS disease progression and HIV variants. The overlapping Nef138-8 and Nef138-10 peptides from the HIV Nef protein are HLA-A24–restricted immunodominant T cell epitopes, and an HIV mutant strain with a Y139F substitution in Nef protein can result in immune escape and is widespread in Japan. Here, we identified a pair of public TCRs specific to the HLA-A24–restricted Nef-138-8 epitope using PBMCs from White and Japanese patients, respectively, namely TD08 and H25-11. The gene use of the variable domain for TD08 and H25-11 is TRAV8-3, TRAJ10 for the α-chain and TRBV7-9, TRBD1*01, TRBJ2-5 for the β-chain. Both TCRs can recognize wild-type and Y2F-mutated Nef138-8 epitopes. We further determined three complex structures, including TD08/HLA-A24-Nef138-8, H25-11/HLA-A24-Nef138-8, and TD08/HLA-A24-Nef138-8 (2F). Then, we revealed the molecular basis of the public TCR binding to the peptide HLA, which mostly relies on the interaction between the TCR and HLA and can tolerate the mutation in the Nef138-8 peptide. These findings promote the molecular understanding of T cell immunity against HIV epitopes and provide an important basis for the engineering of TCRs to develop T cell–based immunotherapy against HIV infection.

Footnotes

This work was supported by the National Key Research and Development Program of China (2021YFC2300700) and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB29010000). Y.S. is also supported by the Youth Innovation Promotion Association of the Chinese Academy of Sciences (Y201921).

The online version of this article contains supplemental material.

S.T., Y.S., and G.F.G. designed and supervised the experiments, K.M., J.G., T.D., and A.K.-T. conducted the experiments. J.Q., Y.C., and K.M. collected the datasets and solved the crystal structures. K.M., S.T., A.I., Y.S., and G.F.G. analyzed the data and wrote the manuscript. All the authors participated in the manuscript editing and discussion.

Abbreviations used in this article:

H bondhydrogen bondHLA-A24HLA-A*24:02PEGpolyethylene glycolpHLApeptide HLASPRsurface plasmon resonanceTRBVT cell receptor β variableReceived March 14, 2022.Accepted August 30, 2022.Copyright © 2022 by The American Association of Immunologists, Inc.