Frolov Ilya, Kim Dal Young, Akhrymuk Maryna, Mobley James A, Frolova Elena I
Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA.
J Virol. 2017 Jun 26;91(14). doi: 10.1128/JVI.00371-17. Print 2017 Jul 15.
Eastern equine encephalitis virus (EEEV) is a representative member of the New World alphaviruses. It is pathogenic for a variety of vertebrate hosts, in which EEEV induces a highly debilitating disease, and the outcomes are frequently lethal. Despite a significant public health threat, the molecular mechanism of EEEV replication and interaction with hosts is poorly understood. Our previously published data and those of other teams have demonstrated that hypervariable domains (HVDs) of the alphavirus nsP3 protein interact with virus-specific host factors and play critical roles in assembly of viral replication complexes (vRCs). The most abundantly represented HVD-binding proteins are the FXR and G3BP family members. FXR proteins drive the assembly of vRCs of Venezuelan equine encephalitis virus (VEEV), and G3BPs were shown to function in vRC assembly in the replication of chikungunya and Sindbis viruses. Our new study demonstrates that EEEV exhibits a unique level of redundancy in the use of host factors in RNA replication. EEEV efficiently utilizes both the VEEV-specific FXR protein family and the Old World alphavirus-specific G3BP protein family. A lack of interaction with either FXRs or G3BPs does not affect vRC formation; however, removal of EEEV's ability to interact with both protein families has a deleterious effect on virus growth. Other identified EEEV nsP3 HVD-interacting host proteins are also capable of supporting EEEV replication, albeit with a dramatically lower efficiency. The ability to use a wide range of host factors with redundant functions in vRC assembly and function provides a plausible explanation for the efficient replication of EEEV and may contribute to its highly pathogenic phenotype. Eastern equine encephalitis virus (EEEV) is one of the most pathogenic New World alphaviruses. Despite the continuous public health threat, to date, the molecular mechanisms of its very efficient replication and high virulence are not sufficiently understood. The results of this new study demonstrate that North American EEEV exhibits a high level of redundancy in using host factors in replication complex assembly and virus replication. The hypervariable domain of the EEEV nsP3 protein interacts with all of the members of the FXR and G3BP protein families, and only a lack of interaction with both protein families strongly affects virus replication rates. Other identified HVD-binding factors are also involved in EEEV replication, but their roles are not as critical as those of FXRs and G3BPs. The new data present a plausible explanation for the exceptionally high replication rates of EEEV and suggest a new means of its attenuation and new targets for screening of antiviral drugs.
东部马脑炎病毒（EEEV）是新大陆甲病毒的代表性成员。它对多种脊椎动物宿主具有致病性，在这些宿主中，EEEV会引发一种使人极度虚弱的疾病，且后果往往是致命的。尽管存在重大的公共卫生威胁，但人们对EEEV复制及其与宿主相互作用的分子机制了解甚少。我们之前发表的数据以及其他团队的数据表明，甲病毒nsP3蛋白的高变区（HVDs）与病毒特异性宿主因子相互作用，并在病毒复制复合体（vRCs）的组装中发挥关键作用。最丰富的HVD结合蛋白是FXR和G3BP家族成员。FXR蛋白驱动委内瑞拉马脑炎病毒（VEEV）的vRCs组装，并且已证明G3BPs在基孔肯雅病毒和辛德毕斯病毒复制的vRC组装中发挥作用。我们的新研究表明，EEEV在RNA复制中利用宿主因子方面表现出独特的冗余水平。EEEV有效地利用了VEEV特异性FXR蛋白家族和旧大陆甲病毒特异性G3BP蛋白家族。与FXRs或G3BPs中的任何一个缺乏相互作用都不会影响vRC的形成；然而，去除EEEV与这两个蛋白家族相互作用的能力会对病毒生长产生有害影响。其他已鉴定的与EEEV nsP3 HVD相互作用的宿主蛋白也能够支持EEEV复制，尽管效率显著较低。在vRC组装和功能中使用具有冗余功能的多种宿主因子的能力，为EEEV的有效复制提供了一个合理的解释，并可能促成其高致病性表型。东部马脑炎病毒（EEEV）是致病性最强的新大陆甲病毒之一。尽管持续存在公共卫生威胁，但迄今为止，其高效复制和高毒力的分子机制尚未得到充分了解。这项新研究的结果表明，北美EEEV在复制复合体组装和病毒复制中使用宿主因子方面表现出高度的冗余性。EEEV nsP3蛋白的高变区与FXR和G3BP蛋白家族的所有成员相互作用，只有与这两个蛋白家族都缺乏相互作用才会强烈影响病毒复制速率。其他已鉴定的HVD结合因子也参与EEEV复制，但其作用不如FXRs和G3BPs关键。这些新数据为EEEV异常高的复制速率提供了一个合理的解释，并提出了一种减弱其毒力的新方法以及筛选抗病毒药物的新靶点。
