Virus Res. 2018 Jul 31. pii: S0168-1702(18)30319-8. doi: 10.1016/j.virusres.2018.07.021. [Epub ahead of print]
Comparison of replication competence of wild-type and lamivudine-resistant hepatitis B virus isolates from a chronic hepatitis B patient.
Zhang Q1, Chen J1, Pan M1, Liu J1, Liu T2, Zhou YH3.
Author information
1
Department of Laboratory Medicine, Nanjing Drum Tower Hospital and Jiangsu Key Laboratory for Molecular Medicine, Nanjing University Medical School, Jiangsu, China.
2
Department of Transfusion Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Jiangsu, China.
3
Department of Laboratory Medicine, Nanjing Drum Tower Hospital and Jiangsu Key Laboratory for Molecular Medicine, Nanjing University Medical School, Jiangsu, China; Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing Medical University, Jiangsu, China. Electronic address: [email protected].
Abstract
In lamivudine-refractory chronic hepatitis B (CHB) patients, discontinuation of lamivudine therapy may lead to loss of lamivudine-resistant hepatitis B virus (HBV) and reappearance of wide-type HBV as dominant strains, yet the underlying mechanism remains unclear. In this study, we cloned wide-type and lamivudine-resistant HBV genomes from the sera of a CHB patient who stopped lamivudine therapy after occurrence of resistant virus and determined the biologic properties of the two isolates in hepatoma cell lines. Sequencing reverse transcriptase region of HBV revealed that the patient developed lamivudine-resistant mutations (rtV173 L, rtL180 M, and rtM204 V) 36 months after the start of lamivudine therapy, and lamivudine-resistant mutants reversed to wild-type after the treatment was stopped for 8 months. Our data showed that the wild-type and mutant isolates had similar transcriptional and translational activity. However, comparison of intracellular and released HBV DNA levels showed that replication efficiency of the mutant virus was approximately 50% of wild-type HBV, while the infectivity of released virus was not affected by the lamivudine-resistant mutations. In conclusion, the reversion of lamivudine-resistant mutants to wild-type HBV after discontinuation of lamivudine in hepatitis B patients may be attributed to better replication fitness of wild-type HBV.
KEYWORDS:
hepatitis B virus; lamivudine-resistance; replication fitness; wild-type