Pilipenko E V, Viktorova E G, Khitrina E V, Maslova S V, Jarousse N, Brahic M, Agol V I
Institute of Poliomyelitis and Viral Encephalitides, Russian Academy of Medical Sciences, Moscow Region 142782, Russia.
J Virol. 1999 Apr;73(4):3190-6. doi: 10.1128/JVI.73.4.3190-3196.1999.
Upon initiation of translation of picornavirus RNA, the ribosome is believed to bind the internal ribosome entry site of the template and then to form a productive complex with a downstream RNA segment, the starting window. The presence or absence of an AUG triplet within the starting window of the RNA of Theiler's murine encephalomyelitis virus (a picornavirus) is known to modulate its neurovirulence. In this study, mutants of this virus in which the starting windows, lying upstream of the viral polyprotein reading frame, had AUGs with different nonoptimal contexts were engineered. Upon intracerebral inoculation of mice, the mutants proved to be partially attenuated, as judged by a significant increase in the dose causing paralysis in 50% of the animals (PD50). Mutants with similar PD50s might differ from one another by eliciting either a severe, fatal tetraplegy or only mild, recoverable neurologic lesions. Some of the mutants triggered a chronic inflammatory reaction in the white matter of the spinal cord in the absence of detectable viral RNA or antigen. Thus, point mutations changing the context of an AUG within the starting window outside the polyprotein reading frame may differently affect the morbidity and mortality caused by a viral infection and may result in distinct attenuation phenotypes.
在微小核糖核酸病毒RNA翻译起始时，核糖体被认为会结合模板的内部核糖体进入位点，然后与下游的RNA片段（起始窗口）形成有功能的复合物。已知泰勒氏小鼠脑脊髓炎病毒（一种微小核糖核酸病毒）RNA的起始窗口内是否存在AUG三联体可调节其神经毒力。在本研究中，构建了该病毒的突变体，其位于病毒多聚蛋白阅读框上游的起始窗口具有不同非最佳上下文的AUG。经脑内接种小鼠后，通过导致50%动物麻痹的剂量（PD50）显著增加判断，这些突变体被证明部分减毒。具有相似PD50的突变体可能因引发严重致命的四联症或仅引发轻度可恢复的神经病变而彼此不同。一些突变体在没有可检测到的病毒RNA或抗原的情况下，在脊髓白质中引发了慢性炎症反应。因此，改变多聚蛋白阅读框外起始窗口内AUG上下文的点突变可能会不同地影响病毒感染引起的发病率和死亡率，并可能导致不同的减毒表型。
