Competitive selection in vivo by a cell for one variant over another: Implications for RNA virus quasispecies in vivo
Competitive selection in vivo by a cell for one variant over another: Implications for RNA virus quasispecies in vivo
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DOI：
10.1128/jvi.70.3.1799-1803.1996
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发表时间：
1996-03-01
影响因子：
5.4
通讯作者：
Oldstone, MBA
中科院分区：
文献类型：
--
作者：
Dockter, J;Evans, CF;Oldstone, MBA
RNA病毒基因组复制的不忠实性导致体外和体内病毒准种的产生。然而，这种产生的变体在体内的生物学意义在很大程度上是未知的和有争议的。为了研究这个问题，我们继续我们的嗜性的淋巴细胞脉络丛脑膜炎病毒（LCMV）变异称为克隆13与其亲本病毒克隆池ARM 53 b（野生型亲本）的神经元细胞在体内的评价。早期的体内和体外研究指出，野生型病毒在糖蛋白（GP）残基260处含有Phe，与神经元嗜性相关，而在残基260处含有Leu的LCMV变体则显示出对免疫系统细胞的选择性嗜性（C. F.埃文斯，P. de la Torre和M. B。A. Oldstone，J. Virol. 68：7367-7373，1994; L. Villarete，T. Somasundaram和R. Ahmed，J. Virol，68：7490-7496，1994）。在此，我们（i）评估了在GP残基260处具有Phe或Leu的病毒变体在脾、肝或脑中体内复制的能力，（ii）分析了在不同比例的两种病毒的单次病毒接种后这些病毒彼此竞争细胞（神经元）特异性选择的能力，以及（iii）利用两种病毒的遗传抑制剂来测试它们在体内神经元中复制的能力。我们发现，在GP残基260处含有Phe或Leu的病毒变体同样能够在神经元中复制，但是当一起接种时，选择在GP残基260处含有Phe的病毒群体的神经元超过在该位置含有Leu的病毒。这与肝和脾中的选择相反，肝和脾中的选择有利于在GP残基260处具有Leu而不是Phe的病毒。对接种病毒抑制剂的分析表明，编码在短RNA上的基因（GP和核蛋白，而不是由大RNA编码的L [聚合酶]和Z蛋白）与嗜神经性相关。由于野生型Armstrong和克隆13的核蛋白序列是相同的，因此神经元的特异性细胞质因子可能在选择在GP残基260处具有Phe的病毒中起重要作用。
Infidelity of genome replication of RNA viruses leads to the generation of viral quasispecies both in vitro and in vivo. However, the biological significance of such generated variants in vivo is largely unknown and controversial. To study this issue, we continued our evaluation of the tropism of a lymphocytic choriomeningitis virus (LCMV) variant termed clone 13 with its parental virus clonal pool ARM 53b (wild-type parent) for neuronal cells in vivo. Earlier in vivo and in vitro studies noted that the wild type virus contained a Phe at glycoprotein (GP) residue 260 which correlated,vith neuron tropism compared with LCMV variants containing a Leu at residue 260 which showed selected tropism for cells of the immune system (C. F. Evans, P. Borrow J. C. de la Torre, and M. B. A. Oldstone, J. Virol. 68:7367-7373, 1994; L. Villarete, T. Somasundaram, and R. Ahmed, J. Virol, 68:7490-7496, 1994). Here we (i) evaluated the ability of the viral variants with either a Phe or Leu at GP residue 260 to replicate in vivo in the spleen, liver, or brain, (ii) analyzed the ability of these viruses to compete against each other for cell (neuron)-specific selection following a single viral inoculation of different ratios of both viruses, and (iii) utilized genetic reassortants of both viruses to test their ability to replicate in neurons in vivo. We found that viral variants containing either a Phe or Leu at GP residue 260 were equally capable of replicating in neurons, but when inoculated together, neurons selected for the viral population containing Phe at GP residue 260 over viruses containing a Leu at this position. This was in contrast to selection in the liver and spleen that favored viruses with Leu and not Phe at GP residue 260. Analysis of inoculations with viral reassortants indicated that genes encoded on the short RNA (the GP and nucleoprotein, not the L [polymerase] and Z proteins that are encoded by the large RNA) were associated with neurotropism. Since the nucleoprotein sequences of wild-type Armstrong and clone 13 are identical, it is likely that specific cytoplasmic factors of the neurons play a fundamental role in the selection of virus with Phe at GP residue 260.