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HBV is a small, partially double-stranded DNA virus that goes through an intricate replication cycle in its native cellular environment: human hepatocytes. A critical step in the viral life-cycle is the conversion of relaxed circular DNA (rcDNA) into covalently closed circular DNA (cccDNA), the latter being the major template for HBV gene transcription. For this conversion, HBV relies on multiple host factors, as enzymes capable of catalyzing the relevant reactions are not encoded in the viral genome. Combinations of genetic and biochemical approaches have produced findings that provide a more holistic picture of the complex mechanism of HBV cccDNA formation. Here, we review some of these studies that have helped to provide a comprehensive picture of rcDNA to cccDNA conversion. Mechanistic insights into this critical step for HBV persistence hold the key for devising new therapies that will lead not only to viral suppression but to a cure.<\/jats:p>","DOI":"10.3390\/v13081463","type":"journal-article","created":{"date-parts":[[2021,7,27]],"date-time":"2021-07-27T22:35:02Z","timestamp":1627425302000},"page":"1463","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":131,"title":["Mechanism of Hepatitis B Virus cccDNA Formation"],"prefix":"10.3390","volume":"13","author":[{"given":"Lei","family":"Wei","sequence":"first","affiliation":[{"name":"110 Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, Washington Road, Princeton, NJ 08544, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Ploss","sequence":"additional","affiliation":[{"name":"110 Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, Washington Road, Princeton, NJ 08544, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s12072-018-9912-8","article-title":"Immunological cure of HBV infection","volume":"13","author":"Lang","year":"2019","journal-title":"Hepatol. 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