Wang Xue-Feng, Liu Qiang, Wang Yu-Hong, Wang Shuai, Chen Jie, Lin Yue-Zhi, Ma Jian, Zhou Jian-Hua, Wang Xiaojun
State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of the Chinese Academy of Agricultural Sciences, Harbin, China.
Department of Geriatrics and Gerontology, First Affiliated Hospital of Harbin Medical University, Harbin, China.
J Virol. 2018 Mar 28;92(8). doi: 10.1128/JVI.02150-17. Print 2018 Apr 15.
The equine infectious anemia virus (EIAV) attenuated vaccine was developed by long-term passaging of a field-isolated virulent strain in cross-species hosts, followed by successive cultivation in cells To explore the molecular mechanism underlying the evolution of the EIAV attenuated vaccine, a systematic study focusing on long-terminal-repeat (LTR) variation in numerous virus strains ranging from virulent EIAV to attenuated EIAV was performed over time both and Two hypervariable regions were identified within the U3 region in the enhancer region (EHR) and the negative regulatory element (NRE) and within the R region in the transcription start site (TSS) and the Tat-activating region (TAR). Among these sites, variation in the U3 region resulted in the formation of additional transcription factor binding sites; this variation of the -adapted strains was consistent with the loss of pathogenicity. Notably, the same LTR variation pattern was observed both and Generally, the LTR variation in both the attenuated virus and the virulent strain fluctuated over time Interestingly, the attenuated-virus-specific LTR variation was also detected in horses infected with the virulent strain, supporting the hypothesis that the evolution of an attenuated virus might have involved branching from EIAV quasispecies. This hypothesis was verified by phylogenetic analysis. The present systematic study examining the molecular evolution of attenuated EIAV from EIAV quasispecies may provide an informative model reflecting the evolution of similar lentiviruses. The attenuated EIAV vaccine was the first lentiviral vaccine used to successfully control for equine infectious anemia in China. This vaccine provides an important reference for studying the relationship between EIAV gene variation and changes in biological characteristics. Importantly, the vaccine provides a model for the investigation of lentiviral quasispecies evolution. This study followed the "natural" development of the attenuated EIAV vaccine by use of a systematic analysis of LTR evolution and The results revealed that the increase in LTR variation with passaging was accompanied by a decrease in virulence, which indicated that LTR variability might parallel the attenuation of virulence. Interestingly, the attenuated-virus-specific LTR variation was also detected in virulent-strain-infected horses, a finding consistent with those of previous investigations of and evolution. Therefore, we present a hypothesis that the evolution of the attenuated virus may involve branching from EIAV quasispecies present .
马传染性贫血病毒（EIAV）减毒疫苗是通过将一株野外分离的强毒株在跨物种宿主中长时间传代，随后在细胞中连续培养而研制出来的。为了探究EIAV减毒疫苗进化的分子机制，我们对从强毒EIAV到减毒EIAV的众多病毒株的长末端重复序列（LTR）变异进行了系统研究，研究在一段时间内同时在体内和体外进行。在增强子区域（EHR）和负调控元件（NRE）的U3区域以及转录起始位点（TSS）和Tat激活区域（TAR）的R区域内鉴定出两个高变区。在这些位点中，U3区域的变异导致形成了额外的转录因子结合位点；这种适应株的变异与致病性的丧失一致。值得注意的是，在体内和体外均观察到相同的LTR变异模式。一般来说，减毒病毒和强毒株中的LTR变异随时间波动。有趣的是，在感染强毒株的马中也检测到了减毒病毒特异性的LTR变异，这支持了减毒病毒的进化可能涉及从EIAV准种分支出来的假说。这一假说通过系统发育分析得到了验证。目前这项从EIAV准种研究减毒EIAV分子进化的系统研究，可能提供一个反映类似慢病毒进化的信息模型。EIAV减毒疫苗是中国首个成功用于控制马传染性贫血的慢病毒疫苗。该疫苗为研究EIAV基因变异与生物学特性变化之间的关系提供了重要参考。重要的是，该疫苗为慢病毒准种进化的研究提供了一个模型。本研究通过对LTR进化进行系统分析，追踪了EIAV减毒疫苗的 “自然” 发展过程。结果表明，随着传代LTR变异增加，毒力下降，这表明LTR变异性可能与毒力减弱平行。有趣的是，在感染强毒株的马中也检测到了减毒病毒特异性的LTR变异，这一发现与之前关于体内和体外进化的研究结果一致。因此，我们提出一个假说，即减毒病毒的进化可能涉及从现存的EIAV准种分支出来。
