{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T04:08:13Z","timestamp":1754021293323,"version":"3.40.5"},"reference-count":39,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2024,7,30]],"date-time":"2024-07-30T00:00:00Z","timestamp":1722297600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The hepatitis B e antigen (HBeAg)\u2010negative infection Phase 3 is characterized by no or minimal signs of hepatic inflammation and the absence of hepatic fibrosis. However, underlying molecular mechanisms leading to this benign phenotype are poorly understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Genotype A, B and D HBeAg\u2010negative patient isolates with precore mutation G1896A from Phase 3 were analysed in comparison with respective HBeAg\u2010positive rescue mutant and HBeAg\u2010positive wild\u2010type reference genomes regarding differences in viral replication, morphogenesis, infectivity and impact on NF\u2010E2\u2010related factor 2 (Nrf2)\/antioxidant response element (ARE)\u2010dependent gene expression and cellular kinome.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In comparison with reference genomes, the patient isolates are characterized by a lower intra\u2010 and extracellular hepatitis B surface antigen (HBsAg)\u2010amount, and HBsAg\u2010retention in the endoplasmic reticulum. Rescue of HBeAg expression increased HBsAg\u2010amount but not its release. Expression of the isolated genomes is associated with a higher Nrf2\/ARE\u2010dependent gene expression as compared to reference genomes independent of HBeAg expression. Kinome analyses revealed a decreased activity of receptors involved in regulation of proliferative pathways for all patient isolates compared to the reference genomes. No specific conserved mutations could be found between all genomes from Phase 3.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>HBeAg\u2010negative genomes from Phase 3 exhibit distinct molecular characteristics leading to lower HBsAg synthesis and release, enhanced oxidative stress protection and decreased activity of key kinases, triggering an antiproliferative stage, which might contribute to the lower probability of hepatocellular carcinoma. The observed differences cannot be associated with loss of HBeAg or specific mutations common to all analysed isolates, indicating the phenotype of Phase 3 derived genomes to be the result of a multifactorial process likely reflecting a conserved natural selection process.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.16048","type":"journal-article","created":{"date-parts":[[2024,7,30]],"date-time":"2024-07-30T12:18:19Z","timestamp":1722341899000},"page":"2773-2792","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Impaired <scp>HBsAg<\/scp> release and antiproliferative\/antioxidant cell regulation by <scp>HBeAg<\/scp>\u2010negative patient isolates reflects an evolutionary process"],"prefix":"10.1111","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6339-1262","authenticated-orcid":false,"given":"Michael","family":"Basic","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and 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