Instability of the HLA-E peptidome of HIV presents a major barrier to therapeutic targeting.

Autor:	Wallace Z; Immunocore Ltd., Abingdon, Oxfordshire OX14 4RY, UK. Electronic address: zoe.wallace@immunocore.com., Heunis T; Immunocore Ltd., Abingdon, Oxfordshire OX14 4RY, UK., Paterson RL; Immunocore Ltd., Abingdon, Oxfordshire OX14 4RY, UK., Suckling RJ; Immunocore Ltd., Abingdon, Oxfordshire OX14 4RY, UK., Grant T; Immunocore Ltd., Abingdon, Oxfordshire OX14 4RY, UK., Dembek M; Immunocore Ltd., Abingdon, Oxfordshire OX14 4RY, UK., Donoso J; Immunocore Ltd., Abingdon, Oxfordshire OX14 4RY, UK., Brener J; Immunocore Ltd., Abingdon, Oxfordshire OX14 4RY, UK., Long J; Immunocore Ltd., Abingdon, Oxfordshire OX14 4RY, UK., Bunjobpol W; Immunocore Ltd., Abingdon, Oxfordshire OX14 4RY, UK., Gibbs-Howe D; Immunocore Ltd., Abingdon, Oxfordshire OX14 4RY, UK., Kay DP; Immunocore Ltd., Abingdon, Oxfordshire OX14 4RY, UK., Leneghan DB; Immunocore Ltd., Abingdon, Oxfordshire OX14 4RY, UK., Godinho LF; Immunocore Ltd., Abingdon, Oxfordshire OX14 4RY, UK., Walker A; Immunocore Ltd., Abingdon, Oxfordshire OX14 4RY, UK., Singh PK; Immunocore Ltd., Abingdon, Oxfordshire OX14 4RY, UK., Knox A; Immunocore Ltd., Abingdon, Oxfordshire OX14 4RY, UK., Leonard S; Immunocore Ltd., Abingdon, Oxfordshire OX14 4RY, UK., Dorrell L; Immunocore Ltd., Abingdon, Oxfordshire OX14 4RY, UK.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2024 Mar 06; Vol. 32 (3), pp. 678-688. Date of Electronic Publication: 2024 Jan 12.
DOI:	10.1016/j.ymthe.2024.01.010
Abstrakt:	Naturally occurring T cells that recognize microbial peptides via HLA-E, a nonpolymorphic HLA class Ib molecule, could provide the foundation for new universal immunotherapeutics. However, confidence in the biological relevance of putative ligands is crucial, given that the mechanisms by which pathogen-derived peptides can access the HLA-E presentation pathway are poorly understood. We systematically interrogated the HIV proteome using immunopeptidomic and bioinformatic approaches, coupled with biochemical and cellular assays. No HIV HLA-E peptides were identified by tandem mass spectrometry analysis of HIV-infected cells. In addition, all bioinformatically predicted HIV peptide ligands (>80) were characterized by poor complex stability. Furthermore, infected cell elimination assays using an affinity-enhanced T cell receptor bispecific targeted to a previously reported HIV Gag HLA-E epitope demonstrated inconsistent presentation of the peptide, despite normal HLA-E expression on HIV-infected cells. This work highlights the instability of the HIV HLA-E peptidome as a major challenge for drug development. Competing Interests: Declaration of interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Z.W., T.H., R.L.P., R.J.S., T.G., M.D., J.D., J.B., J.L., W.B., D.G.-H., D.P.K., D.B.L., L.F.G., A.W., P.K.S., A.K., S.L., and L.D. were/are employees of Immunocore Ltd. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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