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Chronic Hepatitis B virus (HBV) infection is driven in part by T cell dysfunction due to elevated levels of the HBV envelope (Env) protein hepatitis B surface antigen (HBsAg). Here we report the characterization of three genotypic variants of an HLA-E-binding HBsAg peptide, Env<jats:sub>371-379,<\/jats:sub> identified through bioinformatic predictions and verified by biochemical and cellular assays. Using a soluble affinity-enhanced T cell receptor (TCR) (a09b08)-anti-CD3 bispecific molecule to probe HLA-E presentation of the Env<jats:sub>371-379<\/jats:sub> peptides, we demonstrate that only the most stable Env<jats:sub>371-379<\/jats:sub> variant, L6I, elicits functional responses to a09b08-anti-CD3-redirected polyclonal T cells co-cultured with targets expressing endogenous HBsAg. Furthermore, HLA-E-Env<jats:sub>371-379<\/jats:sub> L6I-specific CD8<jats:sup>+<\/jats:sup> T cells are detectable in HBV-na\u00efve donors and people with chronic HBV after in vitro priming. In conclusion, we provide evidence for HLA-E-mediated HBV Env peptide presentation, and highlight the effect of viral mutations on the stability and targetability of pHLA-E molecules.<\/jats:p>","DOI":"10.1038\/s41467-024-54378-9","type":"journal-article","created":{"date-parts":[[2024,11,22]],"date-time":"2024-11-22T10:57:06Z","timestamp":1732273026000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Viral sequence determines HLA-E-restricted T cell recognition of hepatitis B surface antigen"],"prefix":"10.1038","volume":"15","author":[{"given":"Gavuthami","family":"Murugesan","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6268-5947","authenticated-orcid":false,"given":"Rachel L.","family":"Paterson","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1603-4139","authenticated-orcid":false,"given":"Rakesh","family":"Kulkarni","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3968-465X","authenticated-orcid":false,"given":"Veronica","family":"Ilkow","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6962-6533","authenticated-orcid":false,"given":"Richard J.","family":"Suckling","sequence":"additional","affiliation":[]},{"given":"Mary M.","family":"Connolly","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9645-7958","authenticated-orcid":false,"given":"Vijaykumar","family":"Karuppiah","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4980-3707","authenticated-orcid":false,"given":"Robert","family":"Pengelly","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9727-0493","authenticated-orcid":false,"given":"Archana","family":"Jadhav","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8000-1262","authenticated-orcid":false,"given":"Jose","family":"Donoso","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1987-9484","authenticated-orcid":false,"given":"Tiaan","family":"Heunis","sequence":"additional","affiliation":[]},{"given":"Wilawan","family":"Bunjobpol","sequence":"additional","affiliation":[]},{"given":"Gwilym","family":"Philips","sequence":"additional","affiliation":[]},{"given":"Kafayat","family":"Ololade","sequence":"additional","affiliation":[]},{"given":"Daniel","family":"Kay","sequence":"additional","affiliation":[]},{"given":"Anshuk","family":"Sarkar","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9748-6665","authenticated-orcid":false,"given":"Claire","family":"Barber","sequence":"additional","affiliation":[]},{"given":"Ritu","family":"Raj","sequence":"additional","affiliation":[]},{"given":"Carole","family":"Perot","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1177-9388","authenticated-orcid":false,"given":"Tressan","family":"Grant","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5600-8189","authenticated-orcid":false,"given":"Agatha","family":"Treveil","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4715-4325","authenticated-orcid":false,"given":"Andrew","family":"Walker","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2831-3335","authenticated-orcid":false,"given":"Marcin","family":"Dembek","sequence":"additional","affiliation":[]},{"given":"Dawn","family":"Gibbs-Howe","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4353-3738","authenticated-orcid":false,"given":"Miriam","family":"Hock","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7705-1354","authenticated-orcid":false,"given":"Ricardo J.","family":"Carreira","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4214-9450","authenticated-orcid":false,"given":"Kate E.","family":"Atkin","sequence":"additional","affiliation":[]},{"given":"Lucy","family":"Dorrell","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1073-2091","authenticated-orcid":false,"given":"Andrew","family":"Knox","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3752-7300","authenticated-orcid":false,"given":"Sarah","family":"Leonard","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4821-3801","authenticated-orcid":false,"given":"Mariolina","family":"Salio","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2135-5148","authenticated-orcid":false,"given":"Luis F.","family":"Godinho","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2024,11,22]]},"reference":[{"key":"54378_CR1","unstructured":"WHO. 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