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However, effects of these mutations on HBV replication remains controversial. This study aimed to systematically investigate the effect of the mutations on HBV replication and its underlying mechanisms. Using the prcccDNA\/pCMV\u2010Cre recombinant plasmid system, a prcccDNA\u2010A1762T\/G1764A mutant plasmid was constructed. Compared with wild\u2010type HBV, A1762T\/G1764A mutant HBV showed enhanced replication ability with higher secreted HBV DNA and RNA levels, while Southern and Northern blot indicated higher intracellular levels of relaxed circular DNA, single\u2010stranded DNA, and 3.5\u2009kb RNA. Meanwhile, the mutations increased expression of intracellular core protein and decreased the production of HBeAg and HBsAg. In vitro infection based on HepG2\u2010NTCP cells and mice hydrodynamic injection experiment also proved that these mutations promote HBV replication. 5\u2032\u2010RACE assays showed that these mutations upregulated transcription of pregenomic RNA (pgRNA) while downregulating that of preC RNA, which was further confirmed by full\u2010length transcriptome sequencing. Moreover, a proportion of sub\u2010pgRNAs with the potential to express polymerase were also upregulated by these mutations. The ChIP\u2010qPCR assay showed that A1762T\/G1764A mutations created a functional HNF1\u03b1 binding site in the BCP region, and its overexpression enhanced the effect of A1762T\/G1764A mutations on HBV. Our findings revealed the mechanism and importance of A1762T\/G1764A mutations as an indicator for management of CHB patients, and provided HNF1\u03b1 as a new target for curing HBV\u2010infected patients.<\/jats:p>","DOI":"10.1002\/jmv.29129","type":"journal-article","created":{"date-parts":[[2023,9,29]],"date-time":"2023-09-29T09:39:13Z","timestamp":1695980353000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["The A1762T\/G1764A mutations enhance HBV replication by alternating viral transcriptome"],"prefix":"10.1002","volume":"95","author":[{"given":"Danli","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences Peking University Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Zou","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Infectious 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