Venezuelan Equine Encephalitis Virus Variants Lacking Transcription Inhibitory Functions Demonstrate Highly Attenuated Phenotype
Venezuelan Equine Encephalitis Virus Variants Lacking Transcription Inhibitory Functions Demonstrate Highly Attenuated Phenotype
复制标题
DOI：
10.1128/jvi.02252-14
复制
发表时间：
2015-01-01
影响因子：
5.4
通讯作者：
Frolov, Ilya
中科院分区：
文献类型：
--
作者：
Atasheva, Svetlana;Kim, Dal Young;Frolov, Ilya
甲病毒是世界范围内的重大公共卫生威胁。它们通过蚊子传播，引起从严重脑膜脑炎到多发性关节炎的各种人类疾病。迄今为止，还没有针对任何甲病毒感染开发出有效和安全的疫苗。然而，近年来，在理解甲病毒复制和病毒-宿主相互作用的机制方面取得了重大进展。这些数据为开发新的合理设计的甲病毒候选疫苗提供了可能性，这些候选疫苗联合收割机有效的免疫原性、高安全性和不能恢复到致病性表型。在这项研究中设计的委内瑞拉马脑炎病毒（VEEV）的新减毒变体联合收割机各种独立有助于降低毒力的特征。这些构建体编码不能干扰先天性免疫应答的非致细胞病变的VEEV衣壳蛋白。衣壳蛋白特异性突变强烈影响病毒的神经毒力。在其他构建体中，它们与衣壳翻译控制的变化和广泛突变的包装信号相结合。这些修饰也影响了病毒的残留神经毒力，但它仍然具有免疫原性，并且单次免疫保护小鼠免受随后的动物流行VEEV感染。重要信息委内瑞拉马脑炎病毒（VEEV）是一种重要的人类和动物病原体，它会导致高度衰弱性疾病的周期性爆发。尽管持续存在公共卫生威胁，但迄今为止尚未开发出安全有效的候选疫苗。在这项研究中，我们应用积累的知识VEEV复制，RNA包装，与宿主相互作用的机制，设计新的VEEV疫苗候选人，表现出非常高的安全性水平，由于病毒基因组中的广泛修饰的组合。引入的突变不影响RNA复制或结构蛋白的合成，但对VEEV的神经侵袭和毒力产生有害影响。尽管毒力显著降低，但设计的突变体仍具有高度免疫原性，并保护小鼠免受随后的动物流行VEEV感染。类似的方法可用于减毒其他致脑炎的新世界甲病毒。
Alphaviruses represent a significant public health threat worldwide. They are transmitted by mosquitoes and cause a variety of human diseases ranging from severe meningoencephalitis to polyarthritis. To date, no efficient and safe vaccines have been developed against any alphavirus infection. However, in recent years, significant progress has been made in understanding the mechanism of alphavirus replication and virus-host interactions. These data have provided the possibility for the development of new rationally designed alphavirus vaccine candidates that combine efficient immunogenicity, high safety, and inability to revert to pathogenic phenotype. New attenuated variants of Venezuelan equine encephalitis virus (VEEV) designed in this study combine a variety of characteristics that independently contribute to a reduction in virulence. These constructs encode a noncytopathic VEEV capsid protein that is incapable of interfering with the innate immune response. The capsid-specific mutations strongly affect neurovirulence of the virus. In other constructs, they were combined with changes in control of capsid translation and an extensively mutated packaging signal. These modifications also affected the residual neurovirulence of the virus, but it remained immunogenic, and a single immunization protected mice against subsequent infection with epizootic VEEV. Similar approaches of attenuation can be applied to other encephalitogenic New World alphaviruses.IMPORTANCEVenezuelan equine encephalitis virus (VEEV) is an important human and animal pathogen, which causes periodic outbreaks of highly debilitating disease. Despite a continuous public health threat, no safe and efficient vaccine candidates have been developed to date. In this study, we applied accumulated knowledge about the mechanism of VEEV replication, RNA packaging, and interaction with the host to design new VEEV vaccine candidates that demonstrate exceptionally high levels of safety due to a combination of extensive modifications in the viral genome. The introduced mutations did not affect RNA replication or structural protein synthesis but had deleterious effects on VEEV neuroinvasion and virulence. In spite of dramatically reduced virulence, the designed mutants remained highly immunogenic and protected mice against subsequent infection with epizootic VEEV. Similar methodologies can be applied for attenuation of other encephalitogenic New World alphaviruses.