天然存在的核心蛋白突变补偿拉米夫定抗性HBV分离株的复制

StephenW

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

StephenW

抗病毒药物2019年3月19日.pii：S0166-3542（18）30581-3。 doi：10.1016 / j.antiviral.2019.03.006。 [印刷前的电子版]
天然存在的核心蛋白突变补偿拉米夫定抗性HBV分离株的复制适应性降低。
Zhang Y1，Zhang H2，Zhang J2，Zhang J3，Guo H4。
作者信息

1
复旦大学上海医学院附属华山医院感染科，上海
2
印第安纳大学医学院微生物学和免疫学系，美国印第安纳州印第安纳波利斯。
3
复旦大学医学系，上海;复旦大学上海医学院医学分子病毒学重点实验室（MOH＆MOE），上海电子地址：[email protected] .cn。
4
印第安纳大学医学院微生物学和免疫学系，美国印第安纳州印第安纳波利斯。电子地址：[email protected]。

抽象

乙型肝炎病毒（HBV）通过RNA中间体的逆转录复制其DNA基因组。病毒DNA聚合酶缺乏校对能力导致HBV基因组的高突变率。在核苷酸（t）ide翻译（NA）抗病毒药物产生的选择压力下，选择具有抗性突变的病毒。然而，与野生型相比，NA抗性突变体的复制适应性显着降低。 HBV聚合酶的补偿性突变，恢复了病毒的复制能力，已被报道为常见的YMDD耐药突变，该分离株在聚合酶和核心区域具有多个额外的突变。反式实验证明，增强的病毒复制是由于mu核心蛋白的进一步分裂。进一步的诱变研究表明，核心蛋白的P5T突变通过增加衣壳形成和前基因组RNA衣壳化的水平在增强的病毒复制中起重要作用。然而，具有代偿性核心突变的LMV抗性病毒对衣壳组装调节剂（CpAMs）。总之，我们的研究表明，核心突变导致的HBV核衣壳形成增强代表了一种重要的病毒策略，可以克服抗病毒药物的压力，促进病毒的发病机制，CpAMs有望为乙型肝炎开发组合抗病毒治疗。

版权所有©2019。Elsevier B.V.
关键词：

衣壳组装;耐药性;乙型肝炎病毒;复制健身

结论：
30902704
DOI：
10.1016 / j.antiviral.2019.03.006