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Article: Sequence Variations of Full-Length Hepatitis B Virus Genomes in Chinese Patients with HBsAg-Negative Hepatitis B Infection

TitleSequence Variations of Full-Length Hepatitis B Virus Genomes in Chinese Patients with HBsAg-Negative Hepatitis B Infection
Authors
Issue Date2014
Citation
PLoS One, 2014, v. 9 n. 6, p. e99028 How to Cite?
AbstractBACKGROUND: The underlying mechanism of HBsAg-negative hepatitis B virus (HBV) infection is notoriously difficult to elucidate because of the extremely low DNA levels which define the condition. We used a highly efficient amplification method to overcome this obstacle and achieved our aim which was to identify specific mutations or sequence variations associated with this entity. METHODS: A total of 185 sera and 60 liver biopsies from HBsAg-negative, HBV DNA-positive subjects or known chronic hepatitis B (CHB) subjects with HBsAg seroclearance were amplified by rolling circle amplification followed by full-length HBV genome sequencing. Eleven HBsAg-positive CHB subjects were included as controls. The effects of pivotal mutations identified on regulatory regions on promoter activities were analyzed. RESULTS: 22 and 11 full-length HBV genomes were amplified from HBsAg-negative and control subjects respectively. HBV genotype C was the dominant strain. A higher mutation frequency was observed in HBsAg-negative subjects than controls, irrespective of genotype. The nucleotide diversity over the entire HBV genome was significantly higher in HBsAg-negative subjects compared with controls (p = 0.008) and compared with 49 reference sequences from CHB patients (p = 0.025). In addition, HBsAg-negative subjects had significantly higher amino acid substitutions in the four viral genes than controls (all p<0.001). Many mutations were uniquely found in HBsAg-negative subjects, including deletions in promoter regions (13.6%), abolishment of pre-S2/S start codon (18.2%), disruption of pre-S2/S mRNA splicing site (4.5%), nucleotide duplications (9.1%), and missense mutations in "alpha" determinant region, contributing to defects in HBsAg production. CONCLUSIONS: These data suggest an accumulation of multiple mutations constraining viral transcriptional activities contribute to HBsAg-negativity in HBV infection.
Persistent Identifierhttp://hdl.handle.net/10722/198049
ISSN
2015 Impact Factor: 3.057
2015 SCImago Journal Rankings: 1.395
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorHuang, FYen_US
dc.contributor.authorWong, DKHen_US
dc.contributor.authorSeto, WKWen_US
dc.contributor.authorZhang, AYen_US
dc.contributor.authorLee, CKen_US
dc.contributor.authorLin, CKen_US
dc.contributor.authorFung, JYYen_US
dc.contributor.authorLai, CLen_US
dc.contributor.authorYuen, RMFen_US
dc.date.accessioned2014-06-25T02:42:10Z-
dc.date.available2014-06-25T02:42:10Z-
dc.date.issued2014en_US
dc.identifier.citationPLoS One, 2014, v. 9 n. 6, p. e99028en_US
dc.identifier.issn1932-6203en_US
dc.identifier.urihttp://hdl.handle.net/10722/198049-
dc.description.abstractBACKGROUND: The underlying mechanism of HBsAg-negative hepatitis B virus (HBV) infection is notoriously difficult to elucidate because of the extremely low DNA levels which define the condition. We used a highly efficient amplification method to overcome this obstacle and achieved our aim which was to identify specific mutations or sequence variations associated with this entity. METHODS: A total of 185 sera and 60 liver biopsies from HBsAg-negative, HBV DNA-positive subjects or known chronic hepatitis B (CHB) subjects with HBsAg seroclearance were amplified by rolling circle amplification followed by full-length HBV genome sequencing. Eleven HBsAg-positive CHB subjects were included as controls. The effects of pivotal mutations identified on regulatory regions on promoter activities were analyzed. RESULTS: 22 and 11 full-length HBV genomes were amplified from HBsAg-negative and control subjects respectively. HBV genotype C was the dominant strain. A higher mutation frequency was observed in HBsAg-negative subjects than controls, irrespective of genotype. The nucleotide diversity over the entire HBV genome was significantly higher in HBsAg-negative subjects compared with controls (p = 0.008) and compared with 49 reference sequences from CHB patients (p = 0.025). In addition, HBsAg-negative subjects had significantly higher amino acid substitutions in the four viral genes than controls (all p<0.001). Many mutations were uniquely found in HBsAg-negative subjects, including deletions in promoter regions (13.6%), abolishment of pre-S2/S start codon (18.2%), disruption of pre-S2/S mRNA splicing site (4.5%), nucleotide duplications (9.1%), and missense mutations in "alpha" determinant region, contributing to defects in HBsAg production. CONCLUSIONS: These data suggest an accumulation of multiple mutations constraining viral transcriptional activities contribute to HBsAg-negativity in HBV infection.en_US
dc.languageengen_US
dc.relation.ispartofPLoS Oneen_US
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.titleSequence Variations of Full-Length Hepatitis B Virus Genomes in Chinese Patients with HBsAg-Negative Hepatitis B Infectionen_US
dc.typeArticleen_US
dc.identifier.emailHuang, FY: camy@graduate.hku.hken_US
dc.identifier.emailWong, DKH: danywong@hku.hken_US
dc.identifier.emailSeto, WKW: wkseto2@hku.hken_US
dc.identifier.emailFung, JYY: jfung@hkucc.hku.hken_US
dc.identifier.emailLai, CL: hrmelcl@hku.hken_US
dc.identifier.emailYuen, RMF: mfyuen@hku.hken_US
dc.identifier.authorityWong, DKH=rp00492en_US
dc.identifier.authoritySeto, WKW=rp01659en_US
dc.identifier.authorityFung, JYY=rp00518en_US
dc.identifier.authorityYuen, RMF=rp00479en_US
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1371/journal.pone.0099028en_US
dc.identifier.pmid24901840-
dc.identifier.hkuros229437en_US
dc.identifier.volume9en_US
dc.identifier.issue6en_US
dc.identifier.spagee99028en_US
dc.identifier.epagee99028en_US
dc.identifier.isiWOS:000336841400088-

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