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Although humans produce 12 subtypes of interferon-alpha (IFN-\u03b1), IFN-\u03b12a has been the only commonly used treatment against HDV. Previously, we characterized eight HDV genotype isolates with varying replication kinetics. Herein, we systematically investigated the antiviral efficacy of IFN-\u03b12a and other IFN-\u03b1 subtypes against HDV genotypes 1\u20138 during\n                      <jats:italic toggle=\"yes\">de novo<\/jats:italic>\n                      infection, cell mitosis, and in quiescent cells. Our findings revealed that IFN-\u03b12a exhibits potent but varied efficiency against HDV 1\u20138 isolates upon\n                      <jats:italic toggle=\"yes\">de novo<\/jats:italic>\n                      infection and cell mitosis. Conversely, HDVs in resting cells are resistant to IFN-\u03b12a treatment and the IFN-containing cytokine cocktail collected from peripheral blood mononuclear cells stimulated with TLR7\/8 agonist. Mechanistically, both ADAR1 p110 and p150 promote L-HDAg production and inhibit HDV replication. ADAR1 p150, rather than p110, enhances the anti-HDV efficacy of IFN-\u03b1 during\n                      <jats:italic toggle=\"yes\">de novo<\/jats:italic>\n                      infection and cell mitosis, but not in resting cells. Moreover, different subtypes of IFN-\u03b1 exhibit varying anti-HDV activities in both\n                      <jats:italic toggle=\"yes\">de novo<\/jats:italic>\n                      infection and cell mitosis, due to their disparity in activating interferon responses. Among these, IFN-\u03b12a, IFN-\u03b110, and IFN-\u03b114 exhibit the strongest anti-HDV activity and synergize with bulevirtide in suppressing HDV replication. In conclusion, the anti-HDV efficacy of IFN-\u03b1 depends on multiple factors, including HDV genotypes, ADAR1 p150 level, IFN-\u03b1 subtypes, and HDV\u2019s different survival strategies. These findings provide valuable implications for the development and optimization of IFN-based therapies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      Chronic hepatitis delta virus (HDV) infection represents the most severe form of viral hepatitis. This study comprehensively evaluated the antiviral efficacy of interferon-alpha (IFN-\u03b1) subtypes across eight HDV genotypes during\n                      <jats:italic toggle=\"yes\">de novo<\/jats:italic>\n                      infection, cell mitosis, or in quiescent cells. Herein, we found that IFN-\u03b1 exhibits potent but varied efficiency against HDV 1\u20138 isolates upon\n                      <jats:italic toggle=\"yes\">de novo<\/jats:italic>\n                      infection and cell mitosis. Conversely, HDVs in resting cells are resistant to IFN-\u03b1 subtypes, regardless of the cellular ADAR1 levels. Among different subtypes, IFN-\u03b12a, IFN-\u03b110, and IFN-\u03b114 exhibit the strongest anti-HDV activity and synergize with bulevirtide in suppressing HDV replication. These findings provide crucial insights into the optimization of IFN-based monotherapy and combinational therapy against chronic HDV infection.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.01280-25","type":"journal-article","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T13:00:26Z","timestamp":1758200426000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":4,"title":["Multimodal characterization of the responsiveness of eight hepatitis D virus genotype isolates to interferon-alpha treatment"],"prefix":"10.1128","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2544-3882","authenticated-orcid":false,"given":"Yibo","family":"Ding","sequence":"first","affiliation":[{"name":"Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Xuzhou Medical 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