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In the context of a multidisciplinary approach undertaken by the nPOD-Virus group, we assessed VP1 positivity in pancreas and other tissues (spleen, duodenum and pancreatic lymph nodes) from 188 organ donors, including donors with type 1 diabetes and donors expressing autoantibody risk markers. We also investigated whether VP1 positivity is linked to the hyperexpression of HLA class I (HLA-I) molecules in islet cells.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Organ donor tissues were collected by the Network for Pancreatic Organ Donors with Diabetes (nPOD) from donors without diabetes (ND, <jats:italic>n<\/jats:italic>=76), donors expressing a single or multiple diabetes-associated autoantibodies (AAb<jats:sup>+<\/jats:sup>, <jats:italic>n<\/jats:italic>=20; AAb<jats:sup>++<\/jats:sup>, <jats:italic>n<\/jats:italic>=9) and donors with type 1 diabetes with residual insulin-containing islets (T1D-ICIs, <jats:italic>n<\/jats:italic>=41) or only insulin-deficient islets (T1D-IDIs, <jats:italic>n<\/jats:italic>=42). VP1 was assessed using immunohistochemistry (IHC) and HLA-I using IHC and immunofluorescence, in two independent laboratories. We determined assay concordance across laboratories and overall occurrence of positive assays, on a case-by-case basis and between donor groups.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Islet cell VP1 positivity was detected in most T1D-ICI donors (77.5%) vs only 38.2% of ND donors (<jats:italic>p<\/jats:italic>&lt;0.001). VP1 positivity was associated with HLA-I hyperexpression. Of those donors assessed for HLA-I and VP1, 73.7% had both VP1 immunopositivity and HLA-I hyperexpression (<jats:italic>p<\/jats:italic>&lt;0.001 vs ND). Moreover, VP1<jats:sup>+<\/jats:sup> cells were detected at higher frequency in donors with HLA-I hyperexpression (<jats:italic>p<\/jats:italic>&lt;0.001 vs normal HLA-I). Among VP1<jats:sup>+<\/jats:sup> donors, the proportion with HLA-I hyperexpression was significantly higher in the AAb<jats:sup>++<\/jats:sup> and T1D-ICI groups (94.9%, <jats:italic>p<\/jats:italic>&lt;0.001 vs ND); this was not restricted to individuals with recent-onset diabetes. Critically, for all donor groups combined, HLA-I hyperexpression occurred more frequently in VP1<jats:sup>+<\/jats:sup> compared with VP1<jats:sup>\u2212<\/jats:sup> donors (45.8% vs 16%, <jats:italic>p<\/jats:italic>&lt;0.001).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\/interpretation<\/jats:title>\n            <jats:p>We report the most extensive analysis to date of VP1 and HLA-I in pancreases from donors with preclinical and diagnosed type 1 diabetes. We find an association of VP1 with residual beta cells after diagnosis and demonstrate VP1 positivity during the autoantibody-positive preclinical stage. For the first time, we show that VP1 positivity and HLA-I hyperexpression in islet cells are both present during the preclinical stage. While the study of tissues does not allow us to demonstrate causality, our data support the hypothesis that enterovirus infections may occur throughout the natural history of type 1 diabetes and may be one of multiple mechanisms driving islet cell HLA-I hyperexpression.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Graphical Abstract<\/jats:title>\n          <\/jats:sec>","DOI":"10.1007\/s00125-025-06384-9","type":"journal-article","created":{"date-parts":[[2025,3,16]],"date-time":"2025-03-16T23:01:51Z","timestamp":1742166111000},"page":"1197-1210","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Enterovirus VP1 protein and HLA class I hyperexpression in pancreatic islet cells of organ donors with type 1 diabetes"],"prefix":"10.1007","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1531-8583","authenticated-orcid":false,"given":"Teresa","family":"Rodriguez-Calvo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5443-4651","authenticated-orcid":false,"given":"Jutta E.","family":"Laiho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1329-1508","authenticated-orcid":false,"given":"Maarit","family":"Oikarinen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4127-9058","authenticated-orcid":false,"given":"Pouria","family":"Akhbari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Flaxman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2699-2074","authenticated-orcid":false,"given":"Thomas","family":"Worthington","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7550-054X","authenticated-orcid":false,"given":"Paola","family":"Apaolaza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6752-7670","authenticated-orcid":false,"given":"John S.","family":"Kaddis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2614-0813","authenticated-orcid":false,"given":"Irina","family":"Kusmartseva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sisko","family":"Tauriainen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha","family":"Campbell-Thompson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Atkinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"von Herrath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0370-4145","authenticated-orcid":false,"given":"Heikki","family":"Hy\u00f6ty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1537-8113","authenticated-orcid":false,"given":"Noel G.","family":"Morgan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7211-0319","authenticated-orcid":false,"given":"Alberto","family":"Pugliese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1160-6062","authenticated-orcid":false,"given":"Sarah J.","family":"Richardson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the nPOD-Virus group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,17]]},"reference":[{"issue":"Journal Article","key":"6384_CR1","doi-asserted-by":"publisher","first-page":"d35","DOI":"10.1136\/bmj.d35","volume":"342","author":"WCG Yeung","year":"2011","unstructured":"Yeung WCG, Rawlinson WD, Craig ME (2011) Enterovirus infection and type 1 diabetes mellitus: systematic review and meta-analysis of observational molecular studies. 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In addition, appreciation is given to the Organ Procurement Organisations (OPO) who make the nPOD programme possible. The authors would like to thank E. Eskola and E. Tolvanen (Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland), N. Amirian (La Jolla Institute) and D. Balcacean (Helmholtz Munich) for technical assistance. The authors thank all the members of the nPOD-Virus group. A list is included as electronic supplementary material ().","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"Data generated and analysed during this study are available through the corresponding author upon request.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"Open Access funding enabled and organized by Projekt DEAL. This research was performed with the support of the Network for Pancreatic Organ Donors with Diabetes (nPOD; RRID:SCR_014641), a collaborative type 1 diabetes research project supported by grants from Breakthrough T1D (formerly known as JDRF), The Leona M. & Harry B. Helmsley Charitable Trust (3-SRA-2023-1417-S-B) and the Helmsley Charitable Trust (2018PG-T1D053, G-2108-04793). The content and views expressed are the responsibility of the authors and do not necessarily reflect the official view of nPOD. OPO partnering with nPOD to provide research resources are listed at .The nPOD-Virus group was supported by Breakthrough T1D grants (3-SRA-25-2012-516 and 3-SRA-2017-492-A-N) awarded to AP, with sub-awards to members, and the European Commission (Persistent Virus Infection in Diabetes Network [PEVNET], Frame Programme 7, Contract No. 261441). SJR is grateful to Breakthrough T1D for a Career Development Award (5-CDA-2014-221-A-N), to MRC for Project Grant MR\/P010695\/1 (joint with NGM) and is supported by a Steve Morgan Foundation DUK\/JDRF Grant Challenge Senior Research Fellowship (22\/0006504). TRC is grateful to Breakthrough T1D for a Career Development Award (5-CDA-2020-949-A-N). JSK is also supported by a grant from the NIDDK-sponsored Human Islet Research Network (HIRN, RRID:SCR_014393; ; UC24 DK104162). JEL was supported by grants from Sakari and P\u00e4ivikki Sohlberg\u2019s Foundation, Yrj\u00f6 Jahnsson\u2019s Foundation, The Diabetes Research Foundation in Finland and Finnish Cultural foundation. Studies from University of Exeter were supported by the National Institute for Health and Care Research Exeter Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. The studies from Tampere University (HH) were also supported by the European Foundation for the Study of Diabetes (grant no. 97013), Sigrid Juselius Foundation and Academy of Finland (grant no. 288671) and the Diabetes Research Foundation in Finland.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"HH is a board member and stock owner of Vactech Oy, a Finnish biotech company that has contributed to the development of a coxsackie B virus vaccine. MvH is employed by Novo Nordisk A\/S. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"TRC, JEL, JSK, MAA, MvH, HH, NGM, AP and SJR contributed to the original idea. TRC, JEL, MO, PAk, CF, TW, PAp, JSK, IK, ST, MCT, MAA, MvH, HH, NGM, AP and SJR contributed to the design, performance and interpretation of the experiments and formal analysis. TRC, JEL, JSK, AP and SJR wrote the manuscript and it was edited by TRC, JEL, JSK, IK, MAA, HH, NGM, AP and SJR. All authors have read and reviewed the manuscript critically for important intellectual content, and have approved the final version. SJR, TRC, JEL, JSK and AP are the guarantors of this work and, as such, have full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}