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Antiviral Res. 2019 Mar 19. pii: S0166-3542(18)30581-3. doi: 10.1016/j.antiviral.2019.03.006. [Epub ahead of print]
Naturally occurring core protein mutations compensate for the reduced replication fitness of a lamivudine-resistant HBV isolate.
Zhang Y1, Zhang H2, Zhang J2, Zhang J3, Guo H4.
Author information
1
Department of Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
2
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
3
Department of Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China; Key Laboratory of Medical Molecular Virology (MOH & MOE), Shanghai Medical College, Fudan University, Shanghai, China. Electronic address: [email protected].
4
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address: [email protected].
Abstract
Hepatitis B virus (HBV) replicates its DNA genome through reverse transcription of an RNA intermediate. The lack of proofreading capacity of the viral DNA polymerase results in a high mutation rate of HBV genome. Under the selective pressure created by the nucleos(t)ide analogue (NA) antiviral drugs, viruses with resistance mutations are selected. However, the replication fitness of NA-resistant mutants is markedly reduced compared to wild-type. Compensatory mutations in HBV polymerase, which restore the viral replication capacity, have been reported to arise under continuous treatment with lamivudine (LMV). We have previously identified a highly replicative LMV-resistant HBV isolate from a chronic hepatitis B patient experiencing acute disease exacerbation. Besides the common YMDD drug-resistant mutations, this isolate possesses multiple additional mutations in polymerase and core regions. The transcomplementation assay demonstrated that the enhanced viral replication is due to the mutations of core protein. Further mutagenesis study revealed that the P5T mutation of core protein plays an important role in the enhanced viral replication through increasing the levels of capsid formation and pregenomic RNA encapsidation. However, the LMV-resistant virus harboring compensatory core mutations remains sensitive to capsid assembly modulators (CpAMs). Taken together, our study suggests that the enhanced HBV nucleocapsid formation resulting from core mutations represents an important viral strategy to surmount the antiviral drug pressure and contribute to viral pathogenesis, and CpAMs hold promise for developing the combinational antiviral therapy for hepatitis B.
Copyright © 2019. Published by Elsevier B.V.
KEYWORDS:
Capsid assembly; Drug resistance; Hepatitis B virus; Replication fitness
PMID:
30902704
DOI:
10.1016/j.antiviral.2019.03.006
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