Sequence variations of full-length hepatitis B virus genomes in Chinese patients with HBsAg-negative hepatitis B infection

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...

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Veröffentlicht in:	PloS one 2014-06, Vol.9 (6), p.e99028-e99028
Hauptverfasser:	Huang, Fung-Yu, Wong, Danny Ka-Ho, Seto, Wai-Kay, Zhang, An-Ye, Lee, Cheuk-Kwong, Lin, Che-Kit, Fung, James, Lai, Ching-Lung, Yuen, Man-Fung
Format:	Artikel
Sprache:	eng
Schlagworte:	Adult Aged Amino acids Amplification Antigens Biology and Life Sciences Biopsy Blood transfusions China Defects Deoxyribonucleic acid DNA DNA Mutational Analysis DNA sequencing DNA, Viral - chemistry DNA, Viral - metabolism Female Gene expression Gene sequencing Genetic Variation Genome, Viral Genomes Genomics Genotype Genotype & phenotype Health aspects Hepatitis Hepatitis B Hepatitis B surface antigen Hepatitis B Surface Antigens - genetics Hepatitis B virus Hepatitis B virus - classification Hepatitis B virus - genetics Hepatitis B virus - metabolism Hepatitis B, Chronic - diagnosis Hepatitis B, Chronic - virology Hepatology Hospitals Humans Infection Infections Laboratories Liver Liver - pathology Liver - virology Liver cancer Male Medicine Medicine and Health Sciences Middle Aged Missense mutation Mutation Nucleic Acid Conformation Patients Phylogeny Promoter Regions, Genetic Proteins Regulatory sequences RNA RNA, Viral - chemistry Sequence Analysis, DNA Splicing Transcription Viruses
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description	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. 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. 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
doi_str_mv	10.1371/journal.pone.0099028
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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. 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. 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 "α" determinant region, contributing to defects in HBsAg production. 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This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014 Huang et al 2014 Huang et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-54a1b794e3a47d83f480b98c45fccb93fab2d606ba3260a789dcd6ba16f45163</citedby><cites>FETCH-LOGICAL-c692t-54a1b794e3a47d83f480b98c45fccb93fab2d606ba3260a789dcd6ba16f45163</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4047052/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4047052/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24901840$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Huang, Fung-Yu</creatorcontrib><creatorcontrib>Wong, Danny Ka-Ho</creatorcontrib><creatorcontrib>Seto, Wai-Kay</creatorcontrib><creatorcontrib>Zhang, An-Ye</creatorcontrib><creatorcontrib>Lee, Cheuk-Kwong</creatorcontrib><creatorcontrib>Lin, Che-Kit</creatorcontrib><creatorcontrib>Fung, James</creatorcontrib><creatorcontrib>Lai, Ching-Lung</creatorcontrib><creatorcontrib>Yuen, Man-Fung</creatorcontrib><title>Sequence variations of full-length hepatitis B virus genomes in Chinese patients with HBsAg-negative hepatitis B infection</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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. 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. 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 "α" determinant region, contributing to defects in HBsAg production. 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genetics</subject><subject>Hepatitis B virus</subject><subject>Hepatitis B virus - classification</subject><subject>Hepatitis B virus - genetics</subject><subject>Hepatitis B virus - metabolism</subject><subject>Hepatitis B, Chronic - diagnosis</subject><subject>Hepatitis B, Chronic - virology</subject><subject>Hepatology</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Infection</subject><subject>Infections</subject><subject>Laboratories</subject><subject>Liver</subject><subject>Liver - pathology</subject><subject>Liver - virology</subject><subject>Liver cancer</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Middle Aged</subject><subject>Missense mutation</subject><subject>Mutation</subject><subject>Nucleic Acid Conformation</subject><subject>Patients</subject><subject>Phylogeny</subject><subject>Promoter Regions, Genetic</subject><subject>Proteins</subject><subject>Regulatory sequences</subject><subject>RNA</subject><subject>RNA, Viral - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Huang, Fung-Yu</au><au>Wong, Danny Ka-Ho</au><au>Seto, Wai-Kay</au><au>Zhang, An-Ye</au><au>Lee, Cheuk-Kwong</au><au>Lin, Che-Kit</au><au>Fung, James</au><au>Lai, Ching-Lung</au><au>Yuen, Man-Fung</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Sequence variations of full-length hepatitis B virus genomes in Chinese patients with HBsAg-negative hepatitis B infection</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-06-05</date><risdate>2014</risdate><volume>9</volume><issue>6</issue><spage>e99028</spage><epage>e99028</epage><pages>e99028-e99028</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>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. 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. 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 "α" determinant region, contributing to defects in HBsAg production. These data suggest an accumulation of multiple mutations constraining viral transcriptional activities contribute to HBsAg-negativity in HBV infection.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24901840</pmid><doi>10.1371/journal.pone.0099028</doi><oa>free_for_read</oa></addata></record>
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identifier	ISSN: 1932-6203
ispartof	PloS one, 2014-06, Vol.9 (6), p.e99028-e99028
issn	1932-6203 1932-6203
language	eng
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subjects	Adult Aged Amino acids Amplification Antigens Biology and Life Sciences Biopsy Blood transfusions China Defects Deoxyribonucleic acid DNA DNA Mutational Analysis DNA sequencing DNA, Viral - chemistry DNA, Viral - metabolism Female Gene expression Gene sequencing Genetic Variation Genome, Viral Genomes Genomics Genotype Genotype & phenotype Health aspects Hepatitis Hepatitis B Hepatitis B surface antigen Hepatitis B Surface Antigens - genetics Hepatitis B virus Hepatitis B virus - classification Hepatitis B virus - genetics Hepatitis B virus - metabolism Hepatitis B, Chronic - diagnosis Hepatitis B, Chronic - virology Hepatology Hospitals Humans Infection Infections Laboratories Liver Liver - pathology Liver - virology Liver cancer Male Medicine Medicine and Health Sciences Middle Aged Missense mutation Mutation Nucleic Acid Conformation Patients Phylogeny Promoter Regions, Genetic Proteins Regulatory sequences RNA RNA, Viral - chemistry Sequence Analysis, DNA Splicing Transcription Viruses
title	Sequence variations of full-length hepatitis B virus genomes in Chinese patients with HBsAg-negative hepatitis B infection
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