{"doi":"10.1016/j.jcmgh.2022.01.001","title":"A New Model to Assess Hepatitis B Virus Covalently Closed Circular DNA: A Window Into a Previously Hidden Space?","abstract":"Approximately 296 million people are living with chronic hepatitis B infection with 1.5 million new infections each year.1Easterbrook P. Luhmann N. Newman M. Walsh N. Lesi O. Doherty M. New WHO guidance for country validation of viral hepatitis B and C elimination.Lancet Gastroenterol Hepatol. 2021; 6: 778-780Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar Currently approved chronic hepatitis B treatment using nucleoside or nucleotide analogues inhibits hepatitis B virus (HBV) DNA replication and suppresses circulating HBV DNA levels, normalizes liver enzymes, improves histology, reduces hepatocellular carcinoma incidence, and improves overall survival. However, these therapeutic modalities fail to eliminate viral infection, in large measure because they have no meaningful impact on viral covalently closed circular DNA (cccDNA), which exists as a highly stable episomal form in the host nucleus. Moreover, the viral lifecycle replenishes cccDNA stores through recycling of unincorporated nucleocapsids to the nucleus. On the heels of the extraordinarily successful development of curative antiviral agents for treatment of hepatitis C virus, renewed attention has been directed to efforts to bring about sterilizing cure of HBV. However, this challenging task will hinge on successful elimination of cccDNA. Efforts to develop successful curative strategies will in turn rely on development of small animal models that support HBV cccDNA formation and virus production, which has until recently proved elusive. In the past several years, several mouse HBV models supporting cccDNA formation have been constructed using adeno-associated vector (AAV)-mediated transduction of a linearized HBV genome. The AAV-HBV vectors are named by the degree to which their length exceeds the size of the native HBV genome (eg, 1.2 = 1.2-fold), and the HBV nucleotides (nt) at the 5’ and 3’ ends of the linearized genome, the latter designation indicating the site at which the native relaxed circular HBV genome has been linearized. These AAV vectors are AAV-HBV1.2 (nt1354 to nt1989)2Lucifora J. Salvetti A. Marniquet X. Mailly L. Testoni B. Fusil F. Inchauspé A. Michelet M. Michel M.L. Levrero M. Cortez P. Baumert T.F. Cosset F.L. Challier C. Zoulim F. Durantel D. Detection of the hepatitis B virus (HBV) covalently-closed-circular DNA (cccDNA) in mice transduced with a recombinant AAV-HBV vector.Antiviral Res. 2017; 145: 14-19Crossref PubMed Scopus (40) Google Scholar and AAV-HBV1.3 (nt970 to nt2043).3Ko C. Su J. Festag J. Bester R. Kosinska A.D. Protzer U. Intramolecular recombination enables the formation of hepatitis B virus (HBV) cccDNA in mice after HBV genome transfer using recombinant AAV vectors.Antiviral Res. 2021; 194105140Crossref PubMed Scopus (6) Google Scholar,4Wu Y. Zhang T.Y. Fang L.L. Chen Z.X. Song L.W. Cao J.L. Yang L. Yuan Q. Xia N.S. Sleeping Beauty transposon-based system for rapid generation of HBV-replicating stable cell lines.J Virol Methods. 2016; 234: 96-100Crossref PubMed Scopus (9) Google Scholar Both the AAV-HBV linear episome and cccDNA have been consistently replicated and detected in these models, and the AAV-HBV1.2 and 1.3 mouse models have been shown to produce all HBV proteins from its linear episome and cccDNA. These models, which recapitulate the key steps of the viral lifecycle, do not, however, lend themselves to direct assessment of cccDNA, which have traditionally required direct detection of cccDNA in the liver. In this issue of Cellular and Molecular Gastroenterology and Hepatology, Xu et al5Xu Z. Zhao L. Zhong Y. Zhu C. Zhao K. Teng Y. Cheng X. Chen Q. Xia Y. A novel mouse model harboring hepatitis B virus covalently closed circular DNA.Cell Mol Gastroenterol Hepatol. 2022; 13: 1001-1017Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar have now developed an extended and novel mouse model called AAV-HBV1.04 (nt403 to nt538), which by virtue of linearization within the polymerase and s-cod","journal":"Cellular and Molecular Gastroenterology and Hepatology","year":2022,"id":294314,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9538,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":299417,"name":"Wenyu Lin","orcid":"0000-0001-9913-9683","position":1,"is_corresponding":false},{"id":781393,"name":"Raymond Chung","orcid":"0000-0003-0296-5546","position":2,"is_corresponding":false},{"id":237465,"name":"Min Xu","orcid":"0000-0002-0934-1237","position":0,"is_corresponding":true}],"reference_count":7,"raw_metadata":null,"created_at":"2026-07-19T00:31:01.450041Z","pmid":"35085527","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}