Modification of translational control elements as a new approach to design of attenuated picornavirus strains
Modification of translational control elements as a new approach to design of attenuated picornavirus strains
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DOI：
10.1016/0168-1656(95)00088-7
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发表时间：
1996-01-26
影响因子：
4.1
通讯作者：
Slobodskaya, OR
中科院分区：
文献类型：
--
作者：
Agol, VI;Pilipenko, EV;Slobodskaya, OR
不同宿主细胞的翻译机制可能对病毒RNA模板中顺式作用控制元件的特定结构表现出不同的要求。因此，间距适当的寡聚嘧啶/AUG串联（OAT）是皮瘤病毒基因组5'非编码区的保守控制元件，对于Theiler小鼠脑脊髓炎病毒（TMEV）在BHK-21细胞中的生长是必不可少的，但对于该病毒的神经毒力是必不可少的。此外，用启动物AUG取代野生型脊髓灰质炎病毒OAT的隐性（非启动物）AUG片段仅对培养细胞中的病毒繁殖产生轻微影响，而相关突变体的神经毒力则受到显著抑制。这些观察结果使我们能够提出一种合理的方法，通过消除或严重修改宿主基因组中的特异性调节区域来构建新的减毒病毒株。相关的基因重排可能是如此广泛，以至于恢复到毒性表型的可能性应该可以忽略不计。高度减毒和遗传稳定的TMEV和脊髓灰质炎病毒变体的工程可行性被证明。
The translation machineries of different host cells may exhibit varying requirements for a specific structure of cis-acting control elements in the viral RNA templates. Thus, the appropriately spaced oligopyrimidine/AUG tandem (OAT), a conserved control element in the 5' noncoding region of the picomavirus genomes, is dispensable for the growth of Theiler's murine encephalomyelitis virus (TMEV) in BHK-21 cells, but is essential for the neurovirulence of this virus. Also, the replacement of the cryptic (non-initiator) AUG moiety of the wild-type poliovirus OAT by the initiator AUG affects the viral reproduction in cultured cells only slightly, whereas neurovirulence of the relevant mutants is dramatically suppressed. These observations allow us to propose a rational way to construct novel attenuated viral strains by elimination or severe modification of host-specific regulatory regions in their genomes. The relevant genetic rearrangements may be so extensive that the probability of reversion to the virulent phenotype should be negligible. The feasibility of engineering of highly attenuated and genetically stable TMEV and poliovirus variants is illustrated.