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Title: Dynamics of Hepatitis B Virus Quasispecies in Association with Nucleos(t)ide Analogue Treatment Determined by Ultra-Deep Sequencing.
Authors: Nishijima, Norihiro
Marusawa, Hiroyuki  kyouindb  KAKEN_id
Ueda, Yoshihide  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0003-3196-3494 (unconfirmed)
Takahashi, Ken  kyouindb  KAKEN_id
Nasu, Akihiro
Osaki, Yukio
Kou, Tadayuki
Yazumi, Shujiro
Fujiwara, Takeshi
Tsuchiya, Soken
Shimizu, Kazuharu
Uemoto, Shinji  kyouindb  KAKEN_id
Chiba, Tsutomu  kyouindb  KAKEN_id
Author's alias: 西島, 規浩
丸澤, 宏之
Issue Date: 16-Apr-2012
Publisher: Public Library of Science
Journal title: PloS one
Volume: 7
Issue: 4
Thesis number: e35052
Abstract: [Background and Aims]: Although the advent of ultra-deep sequencing technology allows for the analysis of heretofore-undetectable minor viral mutants, a limited amount of information is currently available regarding the clinical implications of hepatitis B virus (HBV) genomic heterogeneity. [Methods]: To characterize the HBV genetic heterogeneity in association with anti-viral therapy, we performed ultra-deep sequencing of full-genome HBV in the liver and serum of 19 patients with chronic viral infection, including 14 therapy-naïve and 5 nucleos(t)ide analogue(NA)-treated cases. [Results]: Most genomic changes observed in viral variants were single base substitutions and were widely distributed throughout the HBV genome. Four of eight (50%) chronic therapy-naïve HBeAg-negative patients showed a relatively low prevalence of the G1896A pre-core (pre-C) mutant in the liver tissues, suggesting that other mutations were involved in their HBeAg seroconversion. Interestingly, liver tissues in 4 of 5 (80%) of the chronic NA-treated anti-HBe-positive cases had extremely low levels of the G1896A pre-C mutant (0.0%, 0.0%, 0.1%, and 1.1%), suggesting the high sensitivity of the G1896A pre-C mutant to NA. Moreover, various abundances of clones resistant to NA were common in both the liver and serum of treatment-naïve patients, and the proportion of M204VI mutants resistant to lamivudine and entecavir expanded in response to entecavir treatment in the serum of 35.7% (5/14) of patients, suggesting the putative risk of developing drug resistance to NA. [Conclusion]: Our findings illustrate the strong advantage of deep sequencing on viral genome as a tool for dissecting the pathophysiology of HBV infection.
Rights: © 2012 Nishijima et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
URI: http://hdl.handle.net/2433/155467
DOI(Published Version): 10.1371/journal.pone.0035052
PubMed ID: 22523569
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