RNA-Dependent RNA Polymerase of the Second Human Pegivirus Exhibits a High-Fidelity Feature.
RNA-Dependent RNA Polymerase of the Second Human Pegivirus Exhibits a High-Fidelity Feature.
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第二种人类 Pegivirus 的 RNA 依赖性 RNA 聚合酶表现出高保真度特征
DOI：
10.1128/spectrum.02729-22
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发表时间：
2022-10-26
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
RNA病毒是人类和动物最重要的病原体，具有快速进化和高适应能力，这是由于在复制过程中使用易出错的RNA依赖RNA聚合酶（RdRp）而具有高突变率。RdRp的保真度与病毒多样性、适应度和发病机制密切相关。病毒编码的RNA依赖RNA聚合酶（RdRp）负责病毒复制，其保真度与病毒的多样性、发病机制、毒力和适应性密切相关。丙型肝炎病毒（HCV）和人类第二培吉病毒（HPgV-2）同属黄病毒科，具有相似的基因组结构等特征。与HCV不同，HPgV-2保留了高度保守的基因组序列和较低的宿主内变异。然而，潜在的机制仍有待阐明。在这项研究中，我们评估了HPgV-2和HCV RdRp在体外RNA聚合酶反应系统中的保真度。结果表明，由于对三磷酸核苷（NTP）底物的识别不同，HPgV-2 RdRp在误掺入率方面比HCV NS5B具有更高的保真度。此外，HPgV-2 RdRp对sofosbuvir（一种抗HCV RdRp的核苷酸抑制剂）的敏感性低于HCV，这解释了HPgV-2对直接作用抗病毒（DAA）治疗HCV感染不敏感。我们的研究结果表明，HPgV-2可能是研究病毒聚合酶保真度以及RNA病毒多样性和进化机制的一个很好的模型。RNA病毒是人类和动物最重要的病原体，具有快速进化和高适应能力，这是由于在复制过程中使用易出错的RNA依赖性RNA聚合酶（RdRp）而具有高突变率。RdRp的保真度与病毒多样性、适应度和发病机制密切相关。先前的研究表明，人类第二佩吉病毒（HPgV-2）具有高度保守的基因组序列和较低的宿主内变异，这可能与HPgV-2 RdRp的保真度有关。在这项工作中，我们使用一系列体外RNA聚合酶检测来评估HPgV-2 RdRp的体外保真度，并将其与HCV RdRp进行比较。结果表明，HPgV-2 RdRp保存的保真度明显高于HCV RdRp，这可能与HPgV-2基因组的保存有关。HPgV-2病毒RdRp保真度的独特特性为研究病毒RdRp保真度提供了一种新的模型。
RNA viruses represent the most important pathogens for humans and animals and exhibit rapid evolution and high adaptive capacity, which is due to the high mutation rates for using the error-prone RNA-dependent RNA polymerase (RdRp) during replication. The fidelity of RdRp is closely associated with viral diversity, fitness, and pathogenesis. ABSTRACT The virus-encoded RNA-dependent RNA polymerase (RdRp) is responsible for viral replication, and its fidelity is closely related to viral diversity, pathogenesis, virulence, and fitness. Hepatitis C virus (HCV) and the second human pegivirus (HPgV-2) belong to the family Flaviviridae and share some features, including similar viral genome structure. Unlike HCV, HPgV-2 preserves a highly conserved genome sequence and low intrahost variation. However, the underlying mechanism remains to be elucidated. In this study, we evaluated the fidelity of HPgV-2 and HCV RdRp in an in vitro RNA polymerase reaction system. The results showed higher fidelity of HPgV-2 RdRp than HCV NS5B with respect to the misincorporation rate due to their difference in recognizing nucleoside triphosphate (NTP) substrates. Furthermore, HPgV-2 RdRp showed lower sensitivity than HCV to sofosbuvir, a nucleotide inhibitor against HCV RdRp, which explained the insusceptibility of HPgV-2 to direct-acting antiviral (DAA) therapy against HCV infection. Our results indicate that HPgV-2 could be an excellent model for studying the mechanisms involved in viral polymerase fidelity as well as RNA virus diversity and evolution. IMPORTANCE RNA viruses represent the most important pathogens for humans and animals and exhibit rapid evolution and high adaptive capacity, which is due to the high mutation rates for using the error-prone RNA-dependent RNA polymerase (RdRp) during replication. The fidelity of RdRp is closely associated with viral diversity, fitness, and pathogenesis. Previous studies have shown that the second human pegivirus (HPgV-2) exhibits a highly conserved genome sequence and low intrahost variation, which might be due to the fidelity of HPgV-2 RdRp. In this work, we used a series of in vitro RNA polymerase assays to evaluate the in vitro fidelity of HPgV-2 RdRp and compared it with that of HCV RdRp. The results indicated that HPgV-2 RdRp preserves significantly higher fidelity than HCV RdRp, which might contribute to the conservation of the HPgV-2 genome. The unique feature of HPgV-2 RdRp fidelity provides a new model for investigation of viral RdRp fidelity.
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影响因子：
6.7
作者：
Pfeiffer JK;Kirkegaard K
通讯作者：
Kirkegaard K
影响因子：
5.6
作者：
Sholders AJ;Peersen OB
通讯作者：
Peersen OB
DOI：
10.1073/pnas.1111650108
发表时间：
2011-09-20
影响因子：
11.1
作者：
Coffey, Lark L.;Beeharry, Yasnee;Vignuzzi, Marco
通讯作者：
Vignuzzi, Marco
影响因子：
6.7
作者：
Levi LI;Gnädig NF;Beaucourt S;McPherson MJ;Baron B;Arnold JJ;Vignuzzi M
通讯作者：
Vignuzzi M
影响因子：
6.4
作者：
Kapoor A;Kumar A;Simmonds P;Bhuva N;Singh Chauhan L;Lee B;Sall AA;Jin Z;Morse SS;Shaz B;Burbelo PD;Lipkin WI
通讯作者：
Lipkin WI