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However, the underlying mechanisms supporting the downregulation of viral replication have yet to be elucidated. In the present study, the analysis of the frequency of subgenotype D1 core protein (HBc) mutations associated with HBeAg status revealed a higher mutation rate in HBeAg\u2010negative sequences compared to HBeAg\u2010positive ones. Particularly, 22 amino acids exhibited a higher frequency of mutation in HBeAg\u2010negative sequences, while the remaining residues showed a high degree of conservation. Subsequently, the assessment of HBc mutants derived from HBeAg\u2010negative patients in viral structure and replicative capacity revealed that HBc mutations have the ability to modulate the subcellular localization of the protein (either when the protein was expressed alone or in the context of viral replication), capsid assembly, and, depending on specific mutation patterns, alter covalently closed circular DNA (cccDNA) recycling and up\u2010 or downregulate viral replication. In conclusion, HBc mutations associated with HBeAg\u2010negative status impact on various stages of the HBV life cycle modulating viral replication during the HBeAg\u2010negative stage of infection.<\/jats:p>","DOI":"10.1002\/jmv.29195","type":"journal-article","created":{"date-parts":[[2023,10,26]],"date-time":"2023-10-26T06:46:11Z","timestamp":1698302771000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Impact of core protein naturally selected mutants associated with HBeAg\u2010negative status in HBV biosynthesis"],"prefix":"10.1002","volume":"95","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0533-4283","authenticated-orcid":false,"given":"Mar\u00eda Mercedes","family":"Elizalde","sequence":"first","affiliation":[{"name":"Facultad de Medicina, Departamento de Microbiolog\u00eda, Parasitolog\u00eda e Inmunolog\u00eda Instituto de Investigaciones Biom\u00e9dicas en Retrovirus y Sida (INBIRS), CONICET, 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