Accumulation of copy-back viral genomes during respiratory syncytial virus infection is preceded by diversification of the copy-back viral genome population followed by selection.
Accumulation of copy-back viral genomes during respiratory syncytial virus infection is preceded by diversification of the copy-back viral genome population followed by selection.
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作者：
RNA病毒在其复制期间产生非标准病毒基因组，包括在没有标准病毒的情况下不能复制的回拷（cbVG）类型的病毒基因组。cbVG在形成病毒感染结果中起着至关重要的作用，因为它们能够干扰病毒复制并诱导强烈的免疫应答。然而，尽管它们在感染过程中起着关键作用，但对驱动病毒群体内cbVG选择和进化的原理知之甚少。由于cbVG依赖于病毒复制机制的产生和复制，我们假设影响病毒复制的宿主因素对cbVG施加选择性压力，并驱动其在病毒群体中的进化。为了验证这一假设，我们使用呼吸道合胞病毒（RSV）作为模型，并通过在免疫活性人肺腺癌A549对照和免疫缺陷A549信号转导和转录激活因子1（STAT 1）KO细胞中连续传代RSV来采取实验进化方法，所述细胞允许更高水平的病毒复制。正如所预测的，我们观察到随着时间的推移，病毒群体在更允许的A549 STAT 1 KO细胞中积累了更高量的cbVG;然而，出乎意料的是，在两种条件下传代后的主要cbVG种类是不同的。虽然A549 STAT 1 KO细胞积累相对较短的cbVG，但A549对照细胞主要含有预测大小长得多的cbVG，这在以前没有描述过。这些长cbVG首先在体外的两种细胞系中占主导地位，并且在RSV感染患者的样品中观察到占主导地位。虽然持续的高复制水平与cbVG的产生和积累有关，但我们的数据表明，持续的高水平病毒复制对cbVG群体多样化至关重要，这是一个先于产生较短cbVG的过程，这些cbVG随着时间的推移选择性地积累。综上所述，我们表明，选择和病毒种群内的cbVG的演变是由如何抵抗或允许一个主机是RSV。
RNA viruses generate nonstandard viral genomes during their replication, including viral genomes of the copy-back (cbVGs) type that cannot replicate in the absence of a standard virus. cbVGs play a crucial role in shaping virus infection outcomes due to their ability to interfere with virus replication and induce strong immune responses. However, despite their critical role during infection, the principles that drive the selection and evolution of cbVGs within a virus population are poorly understood. As cbVGs are dependent on the virus replication machinery to be generated and replicated, we hypothesized that host factors that affect virus replication exert selective pressure on cbVGs and drive their evolution within a virus population. To test this hypothesis, we used respiratory syncytial virus (RSV) as a model and took an experimental evolution approach by serially passaging RSV in immune-competent human lung adenocarcinoma A549 control and immune-deficient A549 Signal transducer and activator of transcription 1 (STAT1) KO cells, which allow higher levels of virus replication. As predicted, we observed that virus populations accumulated higher amounts of cbVGs in the more permissive A549 STAT1 KO cells over time; however, unexpectedly, the predominant cbVG species after passages in the two conditions were different. While A549 STAT1 KO cells accumulated relatively short cbVGs, A549 control cells mainly contained cbVGs of much longer predicted size, which have not been described previously. These long cbVGs were predominant at first in both cell lines in vitro and the predominant ones observed in samples from RSV-infected patients. Although sustained high replication levels are associated with cbVG generation and accumulation, our data show that sustained high levels of virus replication are critical for cbVG population diversification, a process that precedes the generation of shorter cbVGs that selectively accumulate over time. Taken together, we show that selection and evolution of cbVGs within a virus population are shaped by how resistant or permissive a host is to RSV.
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影响因子：
5.4
作者：
Genoyer, Emmanuelle;Lopez, Carolina B.
通讯作者：
Lopez, Carolina B.
影响因子：
5.3
作者：
Johnson KEE;Noval MG;Rangel MV;De Jesus E;Geber A;Schuster S;Cadwell K;Ghedin E;Stapleford KA
通讯作者：
Stapleford KA
DOI：
10.1261/rna.077529.120
发表时间：
2020-12
期刊：
RNA (New York, N.Y.)
影响因子：
--
作者：
Boussier J;Munier S;Achouri E;Meyer B;Crescenzo-Chaigne B;Behillil S;Enouf V;Vignuzzi M;van der Werf S;Naffakh N
通讯作者：
Naffakh N
影响因子：
64.5
作者：
KOLAKOFSKY, D
通讯作者：
KOLAKOFSKY, D
影响因子：
3.7
作者：
KINGSBURY, DW;PORTNER, A;DARLINGTON, RW
通讯作者：
DARLINGTON, RW