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Liver-specific Foxa-deficient mice with hepatic expression of only Foxa3 do not support HBV replication but display biliary epithelial hyperplasia with bridging fibrosis. However, liver-specific Foxa-deficient mice with hepatic expression of only Foxa1 or Foxa2 also successfully restrict viral transcription and replication but display only minimal alterations in liver physiology. These observations suggest that the level of Foxa activity, rather than the combination of specific Foxa genes, is a key determinant of HBV biosynthesis. Together, these findings suggest that targeting Foxa activity could lead to HBV DNA methylation and transcriptional inactivation, resulting in the resolution of chronic HBV infections that are responsible for approximately one million deaths annually worldwide.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>The current absence of curative therapies capable of resolving chronic hepatis B virus (HBV) infection is a major clinical problem associated with considerable morbidity and mortality. The small viral genome limits molecular targets for drug development, suggesting that the identification of cellular factors essential for HBV biosynthesis may represent alternative targets for therapeutic intervention. Genetic Foxa deficiency in the neonatal liver of HBV transgenic mice leads to the transcriptional silencing of viral DNA by CpG methylation without affecting viability or displaying an obvious phenotype. Therefore, limiting liver Foxa activity therapeutically may lead to the methylation of viral covalently closed circular DNA (cccDNA), resulting in its transcriptional silencing and ultimately the resolution of chronic HBV infection.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/jvi.01371-24","type":"journal-article","created":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T15:46:42Z","timestamp":1728402402000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Foxa deficiency restricts hepatitis B virus biosynthesis through epigenic silencing"],"prefix":"10.1128","volume":"98","author":[{"given":"Rachel","family":"Matrenec","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia 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