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. 2024 Mar 6;32(3):678-688.
doi: 10.1016/j.ymthe.2024.01.010. Epub 2024 Jan 12.

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

Zoë Wallace  1 , Tiaan Heunis  2 , Rachel L Paterson  2 , Richard J Suckling  2 , Tressan Grant  2 , Marcin Dembek  2 , Jose Donoso  2 , Jacqui Brener  2 , Joshua Long  2 , Wilawan Bunjobpol  2 , Dawn Gibbs-Howe  2 , Daniel P Kay  2 , Darren B Leneghan  2 , Luis F Godinho  2 , Andrew Walker  2 , Praveen K Singh  2 , Andrew Knox  2 , Sarah Leonard  2 , Lucy Dorrell  2
Affiliations

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

Zoë Wallace et al. Mol Ther. .

Abstract

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.

Keywords: HIV; HLA-E; ImmTAX; T cell; TCR; immunotherapeutic; peptidome.

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Conflict of interest statement

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.

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