This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tacke, F.
Right arrow Articles by Trautwein, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tacke, F.
Right arrow Articles by Trautwein, C.

 Previous Article  |  Next Article 

Journal of Virology, August 2004, p. 8524-8535, Vol. 78, No. 16
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.16.8524-8535.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Basal Core Promoter and Precore Mutations in the Hepatitis B Virus Genome Enhance Replication Efficacy of Lamivudine-Resistant Mutants

Frank Tacke,1 Christina Gehrke,1 Tom Luedde,1 Albert Heim,2 Michael P. Manns,1 and Christian Trautwein1*

Departments of Gastroenterology, Hepatology and Endocrinology,1 Virology, Hannover Medical School, 30625 Hannover, Germany2

Received 22 January 2004/ Accepted 29 March 2004

During chronic hepatitis B virus (HBV) infection, mutations in the precore (PC) or basal core promoter (BCP) region affecting HBV e antigen (HBeAg) expression occur commonly and represent the predominant virus species in patients with HBeAg-negative chronic hepatitis B. The PC mutation (G1896A+C1858T) creates a translational stop codon resulting in absent HBeAg expression, whereas BCP mutations (A1762T/G1764A) reduce HBeAg expression by transcriptional mechanisms. Treatment of chronic HBV infection with lamivudine (LMV) often selects drug-resistant strains with single (rtM204I) or double (rtL180M+rtM204V) point mutations in the YMDD motif of HBV reverse transcriptase. We cloned replication-competent HBV vectors (genotype A, adw2) combining mutations in the core (wild type [wt], PC, and BCP) and polymerase gene (wt, rtM204I, and rtL180M/M204V) and analyzed virus replication and drug sensitivity in vitro. Resistance to LMV (rtM204I/rtL180M+rtM204V) was accompanied by a reduced replication efficacy as evidenced by reduced pregenomic RNA, encapsidated progeny DNA, polymerase activity, and virion release. PC mutations alone did not alter virus replication but restored replication efficacy of the LMV-resistant mutants without affecting drug resistance. BCP mutants had higher replication capacities than did the wt, also in combination with LMV resistance mutations. All nine HBV constructs showed similar sensitivities to adefovir. In conclusion, BCP-PC mutations directly impact the replication capacity of LMV-resistant mutants. PC mutations compensated for replication inefficiency of LMV-resistant mutants, whereas BCP mutations increased viral replication levels to above the wt baseline values, even in LMV-resistant mutants, without affecting drug sensitivity in vitro. Adefovir may be an effective treatment when combinations of core and polymerase mutations occur.

* Corresponding author. Mailing address: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany. Phone: (49) 511-532 6620. Fax: (49) 511-532 4896. E-mail: Trautwein.Christian{at}MH-Hannover.de.

Journal of Virology, August 2004, p. 8524-8535, Vol. 78, No. 16
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.16.8524-8535.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Chou, Y-C, Yu, M-W, Wu, C-F, Yang, S-Y, Lin, C-L, Liu, C-J, Shih, W-L, Chen, P-J, Liaw, Y-F, Chen, C-J (2008). Temporal relationship between hepatitis B virus enhancer II/basal core promoter sequence variation and risk of hepatocellular carcinoma. Gut 57: 91-97 [Abstract] [Full Text]  
  • Lindh, M., Hannoun, C., Malmstrom, S., Lindberg, J., Norkrans, G. (2006). Lamivudine Resistance of Hepatitis B Virus Masked by Coemergence of Mutations in Probe Region of the COBAS AMPLICOR Assay.. J. Clin. Microbiol. 44: 2587-2589 [Abstract] [Full Text]  
  • Tacke, F, Liedtke, C, Bocklage, S, Manns, M P, Trautwein, C (2005). CREB/PKA sensitive signalling pathways activate and maintain expression levels of the hepatitis B virus pre-S2/S promoter. Gut 54: 1309-1317 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»