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

<h4>Background</h4>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...

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Autores principales:	Fung-Yu Huang, Danny Ka-Ho Wong, Wai-Kay Seto, An-Ye Zhang, Cheuk-Kwong Lee, Che-Kit Lin, James Fung, Ching-Lung Lai, Man-Fung Yuen
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5535cc723e744ec1b7c0d251c36fb380
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spelling	oai:doaj.org-article:5535cc723e744ec1b7c0d251c36fb3802021-11-18T08:16:55ZSequence variations of full-length hepatitis B virus genomes in Chinese patients with HBsAg-negative hepatitis B infection.1932-620310.1371/journal.pone.0099028https://doaj.org/article/5535cc723e744ec1b7c0d251c36fb3802014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24901840/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>These data suggest an accumulation of multiple mutations constraining viral transcriptional activities contribute to HBsAg-negativity in HBV infection.Fung-Yu HuangDanny Ka-Ho WongWai-Kay SetoAn-Ye ZhangCheuk-Kwong LeeChe-Kit LinJames FungChing-Lung LaiMan-Fung YuenPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 6, p e99028 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Fung-Yu Huang Danny Ka-Ho Wong Wai-Kay Seto An-Ye Zhang Cheuk-Kwong Lee Che-Kit Lin James Fung Ching-Lung Lai Man-Fung Yuen Sequence variations of full-length hepatitis B virus genomes in Chinese patients with HBsAg-negative hepatitis B infection.
description	<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>These data suggest an accumulation of multiple mutations constraining viral transcriptional activities contribute to HBsAg-negativity in HBV infection.
format	article
author	Fung-Yu Huang Danny Ka-Ho Wong Wai-Kay Seto An-Ye Zhang Cheuk-Kwong Lee Che-Kit Lin James Fung Ching-Lung Lai Man-Fung Yuen
author_facet	Fung-Yu Huang Danny Ka-Ho Wong Wai-Kay Seto An-Ye Zhang Cheuk-Kwong Lee Che-Kit Lin James Fung Ching-Lung Lai Man-Fung Yuen
author_sort	Fung-Yu Huang
title	Sequence variations of full-length hepatitis B virus genomes in Chinese patients with HBsAg-negative hepatitis B infection.
title_short	Sequence variations of full-length hepatitis B virus genomes in Chinese patients with HBsAg-negative hepatitis B infection.
title_full	Sequence variations of full-length hepatitis B virus genomes in Chinese patients with HBsAg-negative hepatitis B infection.
title_fullStr	Sequence variations of full-length hepatitis B virus genomes in Chinese patients with HBsAg-negative hepatitis B infection.
title_full_unstemmed	Sequence variations of full-length hepatitis B virus genomes in Chinese patients with HBsAg-negative hepatitis B infection.
title_sort	sequence variations of full-length hepatitis b virus genomes in chinese patients with hbsag-negative hepatitis b infection.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/5535cc723e744ec1b7c0d251c36fb380
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Sequence variations of full-length hepatitis B virus genomes in Chinese patients with HBsAg-negative hepatitis B infection.

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