{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T20:12:48Z","timestamp":1780603968720,"version":"3.54.1"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,11,16]],"date-time":"2021-11-16T00:00:00Z","timestamp":1637020800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>Human hepatitis Delta virus (HDV) infection is associated to the most severe viral hepatic disease, including severe acute liver decompensation and progression to cirrhosis, and hepatocellular carcinoma. HDV is a satellite of hepatitis B virus (HBV) that requires the HBV envelope proteins for assembly of HDV virions. HDV and HBV exhibit a large genetic diversity that extends, respectively to eight (HDV-1 to -8) and to ten (HBV\/A to\/J) genotypes. Molecular determinants of HDV virion assembly consist of a C-terminal Proline-rich domain in the large Hepatitis Delta Antigen (HDAg) protein, also known as the Delta packaging domain (DPD) and of a Tryptophan-rich domain, the HDV matrix domain (HMD) in the C-terminal region of the HBV envelope proteins. In this study, we performed a systematic genotyping of HBV and HDV in a cohort 1,590 HDV-RNA-positive serum samples collected between 2001 to 2014, from patients originated from diverse parts of the world, thus reflecting a large genetic diversity. Among these samples, 526 HBV (HBV\/A, B, C, D, E, and G) and HDV (HDV-1, 2, 3, and 5 to -8) genotype couples could be obtained. We provide results of a comprehensive analysis of the amino-acid sequence conservation within the HMD and structural and functional features of the DPD that may account for the yet optimal interactions between HDV and its helper HBV.<\/jats:p>","DOI":"10.3389\/fmicb.2021.751531","type":"journal-article","created":{"date-parts":[[2021,11,16]],"date-time":"2021-11-16T07:44:00Z","timestamp":1637048640000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Comprehensive Analysis of Hepatitis Delta Virus Assembly Determinants According to Genotypes: Lessons From a Study of 526 Hepatitis Delta Virus Clinical Strains"],"prefix":"10.3389","volume":"12","author":[{"given":"Athena\u00efs","family":"Gerber","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Le Gal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samira","family":"Dziri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chakib","family":"Alloui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Roulot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"D\u00e9ny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camille","family":"Sureau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9gol\u00e8ne","family":"Brichler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Gordien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,11,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"6350","DOI":"10.1039\/b805087b","article-title":"Another role of proline: stabilization interactions in proteins and protein complexes concerning proline and tryptophane.","volume":"10","author":"Biedermannova","year":"2008","journal-title":"Phys. Chem. Chem. Phys."},{"key":"B2","doi-asserted-by":"publisher","first-page":"11935","DOI":"10.1128\/JVI.00621-06","article-title":"Analysis of the cytosolic domains of the hepatitis B virus envelope proteins for their function in viral particle assembly and infectivity.","volume":"80","author":"Blanchet","year":"2006","journal-title":"J. Virol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1172\/JCI17704","article-title":"In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus.","volume":"112","author":"Bordier","year":"2003","journal-title":"J. Clin. Invest"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1376","DOI":"10.1093\/infdis\/jiaa517","article-title":"No evidence of Hepatitis C Virus (HCV)-assisted Hepatitis D virus propagation in a large cohort of HCV-positive blood donors.","volume":"223","author":"Cappy","year":"2021","journal-title":"J. Infect. Dis."},{"key":"B5","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1002\/hep.31453","article-title":"Preliminary evidence for hepatitis delta Virus exposure in patients who are apparently not infected with Hepatitis B Virus.","volume":"73","author":"Chemin","year":"2021","journal-title":"Hepatology"},{"key":"B6","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1136\/gutjnl-2018-316601","article-title":"Prevalence and burden of hepatitis D virus infection in the global population: a systematic review and meta-analysis.","volume":"68","author":"Chen","year":"2019","journal-title":"Gut"},{"key":"B7","doi-asserted-by":"publisher","first-page":"71","DOI":"10.5501\/wjv.v1.i3.71","article-title":"Molecular and clinical aspects of hepatitis D virus infections.","volume":"1","author":"Dastgerdi","year":"2012","journal-title":"World J. Virol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1114","DOI":"10.1016\/j.jhep.2018.01.029","article-title":"A novel hepatitis B virus species discovered in capuchin monkeys sheds new light on the evolution of primate hepadnaviruses.","volume":"68","author":"de Carvalho Dominguez Souza","year":"2018","journal-title":"J. Hepatol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"6255","DOI":"10.1128\/JVI.00346-14","article-title":"Support of the infectivity of hepatitis delta virus particles by the envelope proteins of different genotypes of hepatitis B virus.","volume":"88","author":"Freitas","year":"2014","journal-title":"J. Virol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1755","DOI":"10.1016\/j.str.2006.09.014","article-title":"Structural insights into the specific binding of huntingtin proline-rich region with the SH3 and WW domains.","volume":"14","author":"Gao","year":"2006","journal-title":"Structure"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1331","DOI":"10.1126\/science.1598578","article-title":"Identification of a prenylation site in delta virus large antigen.","volume":"256","author":"Glenn","year":"1992","journal-title":"Science"},{"key":"B12","doi-asserted-by":"crossref","first-page":"12314","DOI":"10.1128\/JVI.01044-09","article-title":"Clathrin-mediated post-Golgi membrane trafficking in the morphogenesis of hepatitis delta virus.","volume":"83","author":"Huang","year":"2009","journal-title":"J. Virol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"5985","DOI":"10.1128\/JVI.01044-09","article-title":"Large hepatitis delta antigen is a novel clathrin adaptor-like protein.","volume":"81","author":"Huang","year":"2007","journal-title":"J. Virol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1596","DOI":"10.1128\/JVI.02809-06","article-title":"Nuclear export signal-interacting protein forms complexes with lamin A\/C-Nups to mediate the CRM1-independent nuclear export of large hepatitis delta antigen.","volume":"87","author":"Huang","year":"2013","journal-title":"J. Virol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1128\/JVI.02357-12","article-title":"Effect of mutations in the small envelope protein of hepatitis B virus on assembly and secretion of hepatitis delta virus.","volume":"251","author":"Jenna","year":"1998","journal-title":"Virology"},{"key":"B16","doi-asserted-by":"publisher","first-page":"3351","DOI":"10.1006\/viro.1998.9391","article-title":"Mutations in the carboxyl-terminal domain of the small hepatitis B virus envelope protein impair the assembly of hepatitis delta virus particles.","volume":"73","author":"Jenna","year":"1999","journal-title":"J. Virol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"40321","DOI":"10.1128\/JVI.73.4.3351-3358.1999","article-title":"Structure of FBP11 WW1-PL ligand complex reveals the mechanism of proline-rich ligand recognition by group II\/III WW domains.","volume":"281","author":"Kato","year":"2006","journal-title":"J. Biol. Chem."},{"key":"B18","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1096\/fasebj.14.2.231","article-title":"The importance of being proline: the interaction of proline-rich motifs in signaling proteins with their cognate domains.","volume":"14","author":"Kay","year":"2000","journal-title":"FASEB J."},{"key":"B19","doi-asserted-by":"publisher","first-page":"4648","DOI":"10.1128\/JVI.80.10.4648-4655.2006","article-title":"A tryptophan-rich motif in the carboxyl terminus of the small envelope protein of hepatitis B virus is central to the assembly of hepatitis delta virus particles.","volume":"80","author":"Komla-Soukha","year":"2006","journal-title":"J. Virol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1826","DOI":"10.1002\/hep.29574","article-title":"Genetic diversity and worldwide distribution of the deltavirus genus: a study of 2,152 clinical strains.","volume":"66","author":"Le Gal","year":"","journal-title":"Hepatology"},{"key":"B21","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1128\/JCM.02027-16","article-title":"Performance characteristics of a new consensus commercial kit for Hepatitis D Virus RNA viral load quantification.","volume":"55","author":"Le Gal","year":"","journal-title":"J. Clin. Microbiol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"2363","DOI":"10.1128\/JCM.43.5.2363-2369.2005","article-title":"Quantification of hepatitis delta virus RNA in serum by consensus real-time PCR indicates different patterns of virological response to interferon therapy in chronically infected patients.","volume":"43","author":"Le Gal","year":"2005","journal-title":"J. Clin. Microbiol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"8142","DOI":"10.1074\/jbc.M004477200","article-title":"A novel chromosome region maintenance 1-independent nuclear export signal of the large form of hepatitis delta antigen that is required for the viral assembly.","volume":"276","author":"Lee","year":"2001","journal-title":"J. Biol. Chem."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1406","DOI":"10.1128\/JVI.01723-09","article-title":"Multimerization of hepatitis delta antigen is a critical determinant of RNA binding specificity.","volume":"84","author":"Lin","year":"2010","journal-title":"J. Virol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1016\/j.bpg.2017.04.010","article-title":"Natural history of acute and chronic hepatitis B: the role of HBV genotypes and mutants.","volume":"31","author":"Lin","year":"2017","journal-title":"Best Pract. Res. Clin. Gastroenterol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"485","DOI":"10.3851\/IMP2604","article-title":"HBV genotype F: natural history and treatment.","volume":"18","author":"Marciano","year":"2013","journal-title":"Antivir. Ther."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.1002\/jmv.25411","article-title":"Non-F HBV\/HDV-3 coinfection is associated with severe liver disease in Western Brazilian Amazon.","volume":"91","author":"Melo Da Silva","year":"2019","journal-title":"J. Med. Virol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1612","DOI":"10.1128\/jvi.63.4.1612-1618.1989","article-title":"Hepatitis delta virus (HDV) and woodchuck hepatitis virus (WHV) nucleic acids in tissues of HDV-infected chronic WHV carrier woodchucks.","volume":"63","author":"Negro","year":"1989","journal-title":"J. Virol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1111\/jvh.13385","article-title":"Hepatitis delta virus propagation enabled by hepatitis C virus-Scientifically intriguing, but is it relevant to clinical practice?","volume":"28","author":"Pfluger","year":"2021","journal-title":"J. Viral. Hepat."},{"key":"B30","doi-asserted-by":"publisher","first-page":"7152","DOI":"10.3748\/wjg.v20.i23.7152","article-title":"Molecular identification of hepatitis B virus genotypes\/subgenotypes: revised classification hurdles and updated resolutions.","volume":"20","author":"Pourkarim","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2013982118","article-title":"A hepatitis B virus causes chronic infections in equids worldwide.","volume":"118","author":"Rasche","year":"2021","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B32","doi-asserted-by":"publisher","first-page":"17007","DOI":"10.1073\/pnas.1908072116","article-title":"Highly diversified shrew hepatitis B viruses corroborate ancient origins and divergent infection patterns of mammalian hepadnaviruses.","volume":"116","author":"Rasche","year":"2019","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1046","DOI":"10.1016\/j.jhep.2020.06.038","article-title":"Origin, HDV genotype and persistent viremia determine outcome and treatment response in patients with chronic hepatitis delta.","volume":"73","author":"Roulot","year":"2020","journal-title":"J. Hepatol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"2310","DOI":"10.1128\/jvi.66.4.2310-2315.1992","article-title":"Assembly of hepatitis delta virus particles.","volume":"66","author":"Ryu","year":"1992","journal-title":"J. Virol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"3281","DOI":"10.1128\/jvi.67.6.3281-3287.1993","article-title":"Ribonucleoprotein complexes of hepatitis delta virus.","volume":"67","author":"Ryu","year":"1993","journal-title":"J. Virol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"12730","DOI":"10.1128\/JVI.01427-07","article-title":"SH3 binding motif 1 in influenza A virus NS1 protein is essential for PI3K\/Akt signaling pathway activation.","volume":"81","author":"Shin","year":"2007","journal-title":"J. Virol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"36","DOI":"10.5501\/wjv.v4.i2.36","article-title":"Molecular interactions between hepatitis B virus and delta virus.","volume":"4","author":"Shirvani-Dastgerdi","year":"2015","journal-title":"World J. Virol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1016\/j.jhep.2020.04.008","article-title":"The global prevalence of hepatitis D virus infection: systematic review and meta-analysis.","volume":"73","author":"Stockdale","year":"2020","journal-title":"J. Hepatol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/0014-5793(95)00550-S","article-title":"Characterization of a novel protein-binding module\u2013the WW domain.","volume":"369","author":"Sudol","year":"1995","journal-title":"FEBS Lett."},{"key":"B40","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.virol.2005.09.033","article-title":"Hepatitis delta virus.","volume":"344","author":"Taylor","year":"2006","journal-title":"Virology"},{"key":"B41","doi-asserted-by":"publisher","first-page":"2891","DOI":"10.1128\/jvi.61.9.2891-2895.1987","article-title":"Replication of human hepatitis delta virus in primary cultures of woodchuck hepatocytes.","volume":"61","author":"Taylor","year":"1987","journal-title":"J. Virol."},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2020.100060","article-title":"Hepatitis delta virus acts as an immunogenic adjuvant in Hepatitis B virus-infected hepatocytes.","volume":"1","author":"Tham","year":"2020","journal-title":"Cell Rep. Med."},{"key":"B43","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/j.jhep.2021.03.025","article-title":"Assembly and infection efficacy of hepatitis B virus surface protein exchanges in eight hepatitis D virus genotype isolates.","volume":"75","author":"Wang","year":"2021","journal-title":"J. Hepatol."},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1186\/1743-422X-6-31","article-title":"The C-terminal sequence of the large hepatitis delta antigen is variable but retains the ability to bind clathrin.","volume":"6","author":"Wang","year":"2009","journal-title":"Virol. J."},{"key":"B45","doi-asserted-by":"publisher","first-page":"2759","DOI":"10.1099\/vir.0.011239-0","article-title":"Hepatitis delta virus proteins repress hepatitis B virus enhancers and activate the alpha\/beta interferon-inducible MxA gene.","volume":"90","author":"Williams","year":"2009","journal-title":"J. Gen. Virol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1038\/77891","article-title":"Converging on proline: the mechanism of WW domain peptide recognition.","volume":"7","author":"Zarrinpar","year":"2000","journal-title":"Nat. Struct. Biol."}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2021.751531\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,16]],"date-time":"2021-11-16T07:44:03Z","timestamp":1637048643000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2021.751531\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,16]]},"references-count":46,"alternative-id":["10.3389\/fmicb.2021.751531"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2021.751531","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,16]]},"article-number":"751531"}}