{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:03:26Z","timestamp":1785420206338,"version":"3.56.0"},"reference-count":26,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:00:00Z","timestamp":1777507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Research","award":["2022X2KWRK"],"award-info":[{"award-number":["2022X2KWRK"]}]},{"name":"Italian Ministry of Research","award":["P2022WEXP2"],"award-info":[{"award-number":["P2022WEXP2"]}]},{"DOI":"10.13039\/100020098","name":"Innovative Health Initiative","doi-asserted-by":"crossref","award":["101194735"],"award-info":[{"award-number":["101194735"]}],"id":[{"id":"10.13039\/100020098","id-type":"DOI","asserted-by":"crossref"}]},{"award":["101194735"],"award-info":[{"award-number":["101194735"]}],"id":[{"id":"https:\/\/ror.org\/04afqts81","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/019w4f821","id-type":"ROR","asserted-by":"publisher"}]},{"name":"COCIR"},{"id":[{"id":"https:\/\/ror.org\/0315a7e71","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013322","name":"EFPIA","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100013322","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/00g1x4v36","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Europa Bio"},{"name":"MedTech Europe"},{"name":"Vaccines Europe"},{"name":"Roboscreen"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Background &amp; Aim: The entry of Hepatitis D Virus (HDV) depends on HBV surface proteins (HBsAg) composed of three isoforms: large-, middle, and small HBsAg. Here, we investigate the levels of total HBsAg and HBsAg isoforms and their correlations with HDV-RNA, HBcrAg, and transaminases in the setting of untreated chronic hepatitis D (CHD). Methods: This study includes 316 HBeAg-negative patients: 192 CHD and 124 with chronic hepatitis B (CHB) as a control group. HBsAg isoforms were quantified by ad hoc-designed ELISAs. Results: The composition of HBsAg isoforms varied between the two groups of patients, with remarkably higher small HBsAg, middle-HBsAg, and large HBsAg in CHD than in CHB. This data was confirmed by multivariable analysis (p &lt; 0.0001). Among CHD, HBsAg isoforms positively correlated with HDV-RNA (p &lt; 0.0001) and HBcrAg (p &lt; 0.0001) but not with HBV-DNA. The results were confirmed by stratifying patients according to HDV-RNA (&lt; or &gt;1000 IU\/mL) and HBcrAg (&lt; or &gt;3 logU\/mL). Furthermore, CHD patients with ALT &gt; upper limit of normal presented significantly higher S-HBsAg and M-HBsAg levels. Conclusions: CHD is characterized by a more elevated HBsAg isoform production, paralleling HDV-RNA and HBcrAg release. This may suggest a preferential recruitment of HBsAg isoforms in HDV virions at the expense of HBV virions. The association of HBsAg isoforms with higher ALT also suggests their potential contribution in supporting HDV-induced pro-inflammatory stimuli.<\/jats:p>","DOI":"10.3390\/v18050515","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T08:03:47Z","timestamp":1777536227000},"page":"515","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chronic HDV Infection Shows Higher HBsAg Isoform Levels than HBV Infection, Paralleling HDV Replicative Activity"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-9334-8582","authenticated-orcid":false,"given":"Stefano","family":"D\u2019Anna","sequence":"first","affiliation":[{"name":"Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3500-0858","authenticated-orcid":false,"given":"Lorenzo","family":"Piermatteo","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Magnapera","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Grossi","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Tramontozzi","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0327-3875","authenticated-orcid":false,"given":"Antonella","family":"Olivero","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2970-2037","authenticated-orcid":false,"given":"Leonardo","family":"Duca","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Torre","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Teti","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, Infectious Disease Clinic, Tor Vergata University, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1772-196X","authenticated-orcid":false,"given":"Andrea","family":"Di Lorenzo","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, Infectious Disease Clinic, Tor Vergata University, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6561-5298","authenticated-orcid":false,"given":"Vincenzo","family":"Malagnino","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, Infectious Disease Clinic, Tor Vergata University, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6938-8627","authenticated-orcid":false,"given":"Marco","family":"Iannetta","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, Infectious Disease Clinic, Tor Vergata University, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1028-3203","authenticated-orcid":false,"given":"Sandro","family":"Grelli","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy"},{"name":"Virology Unit, Policlinico Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1168-4946","authenticated-orcid":false,"given":"Pierpaolo","family":"Paba","sequence":"additional","affiliation":[{"name":"Virology Unit, Policlinico Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ada","family":"Bertoli","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy"},{"name":"Virology Unit, Policlinico Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Ceccherini-Silberstein","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo","family":"Baiocchi","sequence":"additional","affiliation":[{"name":"Hepatology Unit, Policlinico Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Francioso","sequence":"additional","affiliation":[{"name":"Hepatology Unit, Policlinico Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5704-9890","authenticated-orcid":false,"given":"Ilaria","family":"Lenci","sequence":"additional","affiliation":[{"name":"Hepatology Unit, Policlinico Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Milella","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Human Oncology, Clinic of Infectious Diseases, University of Bari \u201cAldo Moro\u201d, 70121 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annalisa","family":"Saracino","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Human Oncology, Clinic of Infectious Diseases, University of Bari \u201cAldo Moro\u201d, 70121 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9026-6181","authenticated-orcid":false,"given":"Alessia","family":"Ciancio","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppina","family":"Brancaccio","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Health and Health Professions, Universit\u00e0 degli Studi di Roma Link Campus University, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1452-0333","authenticated-orcid":false,"given":"Loredana","family":"Sarmati","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, Infectious Disease Clinic, Tor Vergata University, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1026-7476","authenticated-orcid":false,"given":"Pietro","family":"Lampertico","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Foundation IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"},{"name":"CRC \u201cA. M. and A. Migliavacca\u201d Center for Liver Disease, Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Rizzetto","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0529-9481","authenticated-orcid":false,"given":"Gian Paolo","family":"Caviglia","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2488-2082","authenticated-orcid":false,"given":"Romina","family":"Salpini","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Svicher","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1782","DOI":"10.1136\/gutjnl-2020-323888","article-title":"Hepatitis D Virus in 2021: Virology, Immunology and New Treatment Approaches for a Difficult-to-Treat Disease","volume":"70","author":"Urban","year":"2021","journal-title":"Gut"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Inoue, J., Sato, K., Ninomiya, M., and Masamune, A. 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Viruses, 13.","DOI":"10.3390\/v13061124"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1002\/hep.21112","article-title":"Characterization of a Hepatitis B and Hepatitis Delta Virus Receptor Binding Site","volume":"43","author":"Engelke","year":"2006","journal-title":"Hepatology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2868","DOI":"10.1080\/21505594.2021.1999130","article-title":"Hepatitis B Virus Middle Surface Antigen Loss Promotes Clinical Variant Persistence in Mouse Models","volume":"12","author":"Lin","year":"2021","journal-title":"Virulence"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"199014","DOI":"10.1016\/j.virusres.2022.199014","article-title":"Identification of Neutralizing Epitopes in the PreS2 Domain of the Hepatitis B Virus","volume":"323","author":"Yato","year":"2023","journal-title":"Virus Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"104553","DOI":"10.1016\/j.antiviral.2019.104553","article-title":"Non-Invasive Biomarkers for Chronic Hepatitis B Virus Infection Management","volume":"169","author":"Charre","year":"2019","journal-title":"Antivir. 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Med."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/18\/5\/515\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T04:11:42Z","timestamp":1777695102000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/18\/5\/515"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,30]]},"references-count":26,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["v18050515"],"URL":"https:\/\/doi.org\/10.3390\/v18050515","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,30]]}}}