{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T03:48:09Z","timestamp":1768708089578,"version":"3.49.0"},"reference-count":50,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,2,28]],"date-time":"2024-02-28T00:00:00Z","timestamp":1709078400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011033","name":"Proyectos I+D de Generaci\u00f3n de Conocimiento 2021","doi-asserted-by":"publisher","award":["RTI2018-101936-B-I00"],"award-info":[{"award-number":["RTI2018-101936-B-I00"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011033","name":"Proyectos I+D de Generaci\u00f3n de Conocimiento 2021","doi-asserted-by":"publisher","award":["PID2021-124455OB-I00"],"award-info":[{"award-number":["PID2021-124455OB-I00"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Spanish Ministry of Economy and Competitiveness","award":["RTI2018-101936-B-I00"],"award-info":[{"award-number":["RTI2018-101936-B-I00"]}]},{"name":"Spanish Ministry of Economy and Competitiveness","award":["PID2021-124455OB-I00"],"award-info":[{"award-number":["PID2021-124455OB-I00"]}]},{"name":"FIMA\u2019s AC fellowship","award":["RTI2018-101936-B-I00"],"award-info":[{"award-number":["RTI2018-101936-B-I00"]}]},{"name":"FIMA\u2019s AC fellowship","award":["PID2021-124455OB-I00"],"award-info":[{"award-number":["PID2021-124455OB-I00"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Hepatitis D virus (HDV) infection represents the most severe form of chronic viral hepatitis. We have shown that the delivery of HDV replication-competent genomes to the hepatocytes using adeno-associated virus (AAV-HDV) as gene delivery vehicles offers a unique platform to investigate the molecular aspects of HDV and associated liver damage. For the purpose of this study, we generated HDV genomes modified by site-directed mutagenesis aimed to (i) prevent some post-translational modifications of HDV antigens (HDAgs) such as large-HDAg (L-HDAg) isoprenylation or short-HDAg (S-HDAg) phosphorylation; (ii) alter the localization of HDAgs within the subcellular compartments; and (iii) inhibit the right conformation of the delta ribozyme. First, the different HDV mutants were tested in vitro using plasmid-transfected Huh-7 cells and then in vivo in C57BL\/6 mice using AAV vectors. We found that Ser177 phosphorylation and ribozymal activity are essential for HDV replication and HDAg expression. Mutations of the isoprenylation domain prevented the formation of infectious particles and increased cellular toxicity and liver damage. Furthermore, altering HDAg intracellular localization notably decreased viral replication, though liver damage remained unchanged versus normal HDAg distribution. In addition, a mutation in the nuclear export signal impaired the formation of infectious viral particles. These findings contribute valuable insights into the intricate mechanisms of HDV biology and have implications for therapeutic considerations.<\/jats:p>","DOI":"10.3390\/v16030379","type":"journal-article","created":{"date-parts":[[2024,2,29]],"date-time":"2024-02-29T02:59:39Z","timestamp":1709175579000},"page":"379","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Deciphering the Role of Post-Translational Modifications and Cellular Location of Hepatitis Delta Virus (HDV) Antigens in HDV-Mediated Liver Damage in Mice"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9022-9823","authenticated-orcid":false,"given":"Sheila","family":"Maestro","sequence":"first","affiliation":[{"name":"DNA & RNA Medicine Division, Centro de Investigaci\u00f3n M\u00e9dica Aplicada, University of Navarra, Avenida P\u00edo XII, 31008 Pamplona, Spain"},{"name":"IdiSNA\u2014Instituto de Investigaci\u00f3n Sanitaria de Navarra, 31008 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9924-0965","authenticated-orcid":false,"given":"Nahia","family":"Gomez-Echarte","sequence":"additional","affiliation":[{"name":"DNA & RNA Medicine Division, Centro de Investigaci\u00f3n M\u00e9dica Aplicada, University of Navarra, Avenida P\u00edo XII, 31008 Pamplona, Spain"},{"name":"IdiSNA\u2014Instituto de Investigaci\u00f3n Sanitaria de Navarra, 31008 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gracian","family":"Camps","sequence":"additional","affiliation":[{"name":"DNA & RNA Medicine Division, Centro de Investigaci\u00f3n M\u00e9dica Aplicada, University of Navarra, Avenida P\u00edo XII, 31008 Pamplona, Spain"},{"name":"IdiSNA\u2014Instituto de Investigaci\u00f3n Sanitaria de Navarra, 31008 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6373-2765","authenticated-orcid":false,"given":"Carla","family":"Usai","sequence":"additional","affiliation":[{"name":"DNA & RNA Medicine Division, Centro de Investigaci\u00f3n M\u00e9dica Aplicada, University of Navarra, Avenida P\u00edo XII, 31008 Pamplona, Spain"},{"name":"IdiSNA\u2014Instituto de Investigaci\u00f3n Sanitaria de Navarra, 31008 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Olag\u00fce","sequence":"additional","affiliation":[{"name":"DNA & RNA Medicine Division, Centro de Investigaci\u00f3n M\u00e9dica Aplicada, University of Navarra, Avenida P\u00edo XII, 31008 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4507-8117","authenticated-orcid":false,"given":"Africa","family":"Vales","sequence":"additional","affiliation":[{"name":"DNA & RNA Medicine Division, Centro de Investigaci\u00f3n M\u00e9dica Aplicada, University of Navarra, Avenida P\u00edo XII, 31008 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rafael","family":"Aldabe","sequence":"additional","affiliation":[{"name":"DNA & RNA Medicine Division, Centro de Investigaci\u00f3n M\u00e9dica Aplicada, University of Navarra, Avenida P\u00edo XII, 31008 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1600-4562","authenticated-orcid":false,"given":"Gloria","family":"Gonzalez-Aseguinolaza","sequence":"additional","affiliation":[{"name":"DNA & RNA Medicine Division, Centro de Investigaci\u00f3n M\u00e9dica Aplicada, University of Navarra, Avenida P\u00edo XII, 31008 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,28]]},"reference":[{"key":"ref_1","unstructured":"(2024, February 19). 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