{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:21:35Z","timestamp":1760235695087,"version":"build-2065373602"},"reference-count":48,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,9,17]],"date-time":"2021-09-17T00:00:00Z","timestamp":1631836800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["17fk0310105h0001"],"award-info":[{"award-number":["17fk0310105h0001"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Hepatitis B virus (HBV) is a major pathogen that causes acute\/chronic hepatitis. Continuous HBV infection can lead to the development of hepatocellular carcinoma (HCC). Although several different anti-HBV treatments are available for chronic hepatitis B patients, discontinuing these medications is difficult. Patients with chronic hepatitis B at high risk for HCC therefore require close observation. However, no suitable biomarkers for detecting high-risk groups for HCC exist, except for serum HBV-DNA, but a number of HCC biomarkers are used clinically, such as alpha-fetoprotein (AFP) and protein induced by vitamin K absence-II (PIVKA-II). Glycosylation is an important post-translational protein modification involved in many human pathologic conditions. HBV surface proteins contain various oligosaccharides, and several reports have described their biological functions. Inhibition of HBV glycosylation represents a potential novel anti-HBV therapy. It is thought that glycosylation of hepatocytes\/hepatoma cells is also important for HBV infection, as it prevents HBV from infecting cells other than hepatocytes, even if the cells express the HBV receptor. In this review, we summarize considerable research regarding the relationship between HBV and glycosylation as it relates to the development of novel diagnostic tests and therapies for HBV.<\/jats:p>","DOI":"10.3390\/v13091860","type":"journal-article","created":{"date-parts":[[2021,9,22]],"date-time":"2021-09-22T03:47:35Z","timestamp":1632282455000},"page":"1860","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Challenges in the Application of Glyco-Technology to Hepatitis B Virus Therapy and Diagnosis"],"prefix":"10.3390","volume":"13","author":[{"given":"Tsunenori","family":"Ouchida","sequence":"first","affiliation":[{"name":"Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, 1-7 Yamada-oka, Suita 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1996-7740","authenticated-orcid":false,"given":"Shinji","family":"Takamatsu","sequence":"additional","affiliation":[{"name":"Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, 1-7 Yamada-oka, Suita 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megumi","family":"Maeda","sequence":"additional","affiliation":[{"name":"Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, 1-7 Yamada-oka, Suita 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatsuya","family":"Asuka","sequence":"additional","affiliation":[{"name":"Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, 1-7 Yamada-oka, Suita 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiharu","family":"Morita","sequence":"additional","affiliation":[{"name":"Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, 1-7 Yamada-oka, Suita 565-0871, Japan"},{"name":"Department of Microbiology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jumpei","family":"Kondo","sequence":"additional","affiliation":[{"name":"Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, 1-7 Yamada-oka, Suita 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5641-8105","authenticated-orcid":false,"given":"Keiji","family":"Ueda","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9430-2362","authenticated-orcid":false,"given":"Eiji","family":"Miyoshi","sequence":"additional","affiliation":[{"name":"Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, 1-7 Yamada-oka, Suita 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,17]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2017). Global Hepatitis Report, World Health Organization."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Rybicka, M., and Bielawski, K.P. (2020). Recent advances in understanding, diagnosing, and treating hepatitis B virus infection. Microorganisms, 8.","DOI":"10.3390\/microorganisms8091416"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"a024935","DOI":"10.1101\/cshperspect.a024935","article-title":"Viral hepatitis B: Clinical and epidemiological characteristics","volume":"4","author":"Burns","year":"2014","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1111\/apt.15581","article-title":"Review article: Clinical pharmacology of current and investigational hepatitis B virus therapies","volume":"51","author":"Smolders","year":"2020","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e00049","DOI":"10.7554\/eLife.00049","article-title":"Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus","volume":"1","author":"Yan","year":"2012","journal-title":"eLife"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/978-981-13-9151-4_5","article-title":"Cell culture models and animal models for HBV study","volume":"1179","author":"Li","year":"2020","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"9049","DOI":"10.1128\/JVI.01161-14","article-title":"Modification of the hepatitis B virus envelope protein glycosylation pattern interferes with secretion of viral particles, infectivity, and susceptibility to neutralizing antibodies","volume":"88","author":"Julithe","year":"2014","journal-title":"J. Virol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1016\/j.jhep.2008.12.010","article-title":"Alteration of protein glycosylation in liver diseases","volume":"50","author":"Blomme","year":"2009","journal-title":"J. Hepatol."},{"key":"ref_9","first-page":"1544","article-title":"The importance of glycans of viral and host proteins in enveloped virus infection","volume":"12","author":"Li","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1093\/glycob\/cwv091","article-title":"Symbol nomenclature for graphical representations of glycans","volume":"25","author":"Varki","year":"2015","journal-title":"Glycobiology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1038\/nrc3982","article-title":"Glycosylation in cancer: Mechanisms and clinical implications","volume":"15","author":"Pinho","year":"2015","journal-title":"Nat. Rev. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1093\/jb\/mvn011","article-title":"Biological function of fucosylation in cancer biology","volume":"143","author":"Miyoshi","year":"2008","journal-title":"J. Biochem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1093\/glycob\/cwn071","article-title":"N-Glycans in cancer progression","volume":"18","author":"Lau","year":"2008","journal-title":"Glycobiology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1111\/hepr.13459","article-title":"Functional glycomics: Application to medical science and hepatology","volume":"50","author":"Miyoshi","year":"2020","journal-title":"Hepatol. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1007\/s00535-014-1007-2","article-title":"Association between Wisteria floribunda agglutinin-positive Mac-2 binding protein and the fibrosis stage of non-alcoholic fatty liver disease","volume":"50","author":"Abe","year":"2015","journal-title":"J. Gastroenterol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1007\/s10545-016-0012-4","article-title":"Liver involvement in congenital disorders of glycosylation (CDG). A systematic review of the literature","volume":"40","author":"Ferreira","year":"2017","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1038\/s41581-019-0129-4","article-title":"Glycosylation in health and disease","volume":"15","author":"Reily","year":"2019","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1007\/s00277-021-04489-w","article-title":"Association between ABO blood types and coronavirus disease 2019 (COVID-19), genetic associations, and underlying molecular mechanisms: A literature review of 23 studies","volume":"100","author":"Zhang","year":"2021","journal-title":"Ann. Hematol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1038\/nmeth803","article-title":"Evanescent-field fluorescence-assisted lectin microarray: A new strategy for glycan profiling","volume":"2","author":"Kuno","year":"2005","journal-title":"Nat. Methods"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4097","DOI":"10.1021\/acs.jproteome.8b00515","article-title":"Current technologies for complex glycoproteomics and their applications to biology\/disease-driven glycoproteomics","volume":"17","author":"Narimatsu","year":"2018","journal-title":"J. Proteome Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3257","DOI":"10.1002\/pmic.200800046","article-title":"Fucosylated haptoglobin is a novel marker for pancreatic cancer: Detailed analyses of oligosaccharide structures","volume":"8","author":"Miyoshi","year":"2008","journal-title":"Proteomics"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1128\/jvi.52.2.396-402.1984","article-title":"Large surface proteins of hepatitis B virus containing the pre-s sequence","volume":"52","author":"Heermann","year":"1984","journal-title":"J. Virol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1159\/000149993","article-title":"Immunogenicity of the gene S and pre-S domains in hepatitis B virions and HBsAg filaments","volume":"28","author":"Heermann","year":"1987","journal-title":"Intervirology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"65","DOI":"10.3748\/wjg.v13.i1.65","article-title":"Hepatitis B virus morphogenesis","volume":"13","author":"Bruss","year":"2007","journal-title":"World J. Gastroenterol. WJG"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.1099\/vir.0.79932-0","article-title":"Structure of pre-S2 N- and O-linked glycans in surface proteins from different genotypes of hepatitis B virus","volume":"85","author":"Schmitt","year":"2004","journal-title":"J. Gen. Virol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5519","DOI":"10.1128\/JVI.77.9.5519-5523.2003","article-title":"Role of N glycosylation of hepatitis B virus envelope proteins in morphogenesis and infectivity of hepatitis delta virus","volume":"77","author":"Sureau","year":"2003","journal-title":"J. Virol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/j.jhep.2013.11.004","article-title":"N-glycosylation mutations within hepatitis B virus surface major hydrophilic region contribute mostly to immune escape","volume":"60","author":"Yu","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2380","DOI":"10.1073\/pnas.94.6.2380","article-title":"Aberrant trafficking of hepatitis B virus glycoproteins in cells in which N-glycan processing is inhibited","volume":"94","author":"Lu","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"697","DOI":"10.3389\/fmicb.2020.00697","article-title":"SERINC5 Inhibits the Secretion of complete and genome-free hepatitis B virions through interfering with the glycosylation of the HBV envelope","volume":"11","author":"Liu","year":"2020","journal-title":"Front. Microbiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"61719","DOI":"10.18632\/oncotarget.18682","article-title":"Additional N-glycosylation mutation in the major hydrophilic region of hepatitis B virus S gene is a risk indicator for hepatocellular carcinoma occurrence in patients with coexistence of HBsAg\/anti-HBs","volume":"8","author":"Qiao","year":"2017","journal-title":"Oncotarget"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.jcv.2016.06.018","article-title":"PreS deletion profiles of hepatitis B virus (HBV) are associated with clinical presentations of chronic HBV infection","volume":"82","author":"Li","year":"2016","journal-title":"J. Clin. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"100144","DOI":"10.1016\/j.jhepr.2020.100144","article-title":"Hepatitis B virus preS2\u039438\u201355 variants: A newly identified risk factor for hepatocellular carcinoma","volume":"2","author":"Cohen","year":"2020","journal-title":"JHEP Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1073\/pnas.0408928102","article-title":"Use of targeted glycoproteomics to identify serum glycoproteins that correlate with liver cancer in woodchucks and humans","volume":"102","author":"Block","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1016\/j.jhep.2005.05.028","article-title":"GP73, a resident Golgi glycoprotein, is a novel serum marker for hepatocellular carcinoma","volume":"43","author":"Marrero","year":"2005","journal-title":"J. Hepatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5857","DOI":"10.1002\/pmic.200500707","article-title":"Identification and analysis of altered \u03b11,6-fucosylated glycoproteins associated with hepatocellular carcinoma metastasis","volume":"6","author":"Dai","year":"2006","journal-title":"Proteomics"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1007\/s00535-017-1425-z","article-title":"Mac-2 binding protein glycan isomer (M2BPGi) is a new serum biomarker for assessing liver fibrosis: More than a biomarker of liver fibrosis","volume":"53","author":"Shirabe","year":"2018","journal-title":"J. Gastroenterol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1002\/hep4.1321","article-title":"Mac-2 binding protein glycosylation isomer as a hepatocellular carcinoma marker in patients with chronic hepatitis B or C infection","volume":"3","author":"Jun","year":"2019","journal-title":"Hepatol. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Baudi, I., Inoue, T., and Tanaka, Y. (2020). Novel biomarkers of hepatitis B and hepatocellular carcinoma: Clinical significance of HBcrAg and M2BPGi. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21030949"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1957","DOI":"10.1038\/s41598-017-02158-5","article-title":"Favorable response to long-term nucleos(t)ide analogue therapy in HBeAg-positive patients with high serum fucosyl-agalactosyl IgG","volume":"7","author":"Ho","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Appelman, M.D., Chakraborty, A., Protzer, U., McKeating, J.A., and Graaf, S.F.J. (2017). van de N-Glycosylation of the Na+-Taurocholate Cotransporting Polypeptide (NTCP) determines its trafficking and stability and is required for hepatitis B virus infection. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0170419"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1002\/hep4.1174","article-title":"Age-dependent glycosylation of the sodium taurocholate cotransporter polypeptide: From fetal to adult human livers","volume":"2","author":"Sargiacomo","year":"2018","journal-title":"Hepatol. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"74","DOI":"10.3389\/fcimb.2020.00074","article-title":"E-cadherin plays a role in hepatitis B virus entry through affecting glycosylated sodium-taurocholate cotransporting polypeptide distribution","volume":"10","author":"Hu","year":"2020","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"8487","DOI":"10.1073\/pnas.1811064116","article-title":"Epidermal growth factor receptor is a host-entry cofactor triggering hepatitis B virus internalization","volume":"116","author":"Iwamoto","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","first-page":"1180","article-title":"Core-fucosylation plays a pivotal role in hepatitis B pseudo virus infection: A possible implication for HBV glycotherapy","volume":"26","author":"Takamatsu","year":"2016","journal-title":"Glycobiology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1073\/pnas.84.2.444","article-title":"Stable expression and replication of hepatitis B virus genome in an integrated state in a human hepatoma cell line transfected with the cloned viral DNA","volume":"84","author":"Tsurimoto","year":"1987","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Wu, C.-S., Lee, T.-Y., Chou, R.-H., Yen, C.-J., Huang, W.-C., Wu, C.-Y., and Yu, Y.-L. (2014). Development of a highly sensitive glycan microarray for quantifying AFP-L3 for early prediction of hepatitis B virus\u2013related hepatocellular carcinoma. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0099959"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1093\/glycob\/cwx075","article-title":"Core fucose is critical for CD14-dependent Toll-like receptor 4 signaling","volume":"27","author":"Iijima","year":"2017","journal-title":"Glycobiology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1080\/19420862.2018.1466767","article-title":"The \u201cless-is-more\u201d in therapeutic antibodies: Afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity","volume":"10","author":"Pereira","year":"2018","journal-title":"mAbs"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/9\/1860\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:01:30Z","timestamp":1760166090000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/9\/1860"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,17]]},"references-count":48,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["v13091860"],"URL":"https:\/\/doi.org\/10.3390\/v13091860","relation":{},"ISSN":["1999-4915"],"issn-type":[{"type":"electronic","value":"1999-4915"}],"subject":[],"published":{"date-parts":[[2021,9,17]]}}}