Influenza Virus Reassortment Is Enhanced by Semi-infectious Particles but Can Be Suppressed by Defective Interfering Particles.
Influenza Virus Reassortment Is Enhanced by Semi-infectious Particles but Can Be Suppressed by Defective Interfering Particles.
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DOI：
10.1371/journal.ppat.1005204
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发表时间：
2015-10
期刊：
影响因子：
6.7
通讯作者：
Lowen AC
中科院分区：
文献类型：
--
作者：
Fonville JM;Marshall N;Tao H;Steel J;Lowen AC
高颗粒与感染性比率是许多RNA病毒的共同特征，约90-99%的颗粒在低多样性条件下不能启动生产性感染。布鲁克等人最近的出版物揭示，对于甲型流感病毒（IAV），这些看似非感染性的颗粒中的一部分实际上是半感染性的。半感染性（SI）颗粒向细胞递送不完整的病毒基因组，因此除非通过共感染补充，否则不能支持完整的复制周期。除SI颗粒外，IAV群体通常含有缺陷干扰（DI）颗粒，其积极干扰感染性子代的产生。为了了解这些不完整的颗粒对病毒进化的意义，我们测试了SI和DI颗粒通过重配促进多样化的假设。我们的方法结合了计算模拟与实验测定的感染，共感染和重组水平共同接种培养细胞与两种不同的流感A/巴拿马/2007/99（H3 N2）为基础的病毒。计算结果预测，在给定的%感染或多重感染，随着半感染性颗粒含量的增加，重组增强。实验数据与模型的比较表明，给定片段缺失的可能性在片段之间存在差异，并且大多数颗粒未能递送≥1个片段。为了验证SI颗粒增强重配的预测，我们使用暴露于低剂量UV的病毒进行共感染。正如预期的那样，引入半感染性颗粒与紫外线诱导的病变增强重配。与SI颗粒相反，在建模的病毒群体中包含DI颗粒不能解释观察到的重配结果。此外，实验发现DI颗粒抑制可检测的重配，相对于标准病毒原液所见，最有可能是通过干扰来自共感染细胞的感染性子代的产生。这些数据表明，半感染性颗粒增加了重组率，因此可能加速IAV的适应性进化。由于甲型流感病毒的基因组有八个不连续的片段，因此两种甲型流感病毒在感染同一细胞时可以很容易地交换基因。这种重组过程对病毒的进化很重要，也是这种病原体不断变化的原因之一。人们早就知道，流感病毒和许多其他RNA病毒产生的病毒颗粒中有很大一部分并不具有完全的传染性，但这些颗粒的生物学意义仍然不清楚。在这里，我们表明，病毒颗粒，提供不完整的基因组的细胞提高重组率。因此，尽管它们产生子代病毒的潜力有限，但这些不完整的颗粒可能在病毒进化中发挥重要作用。
A high particle to infectivity ratio is a feature common to many RNA viruses, with ~90–99% of particles unable to initiate a productive infection under low multiplicity conditions. A recent publication by Brooke et al. revealed that, for influenza A virus (IAV), a proportion of these seemingly non-infectious particles are in fact semi-infectious. Semi-infectious (SI) particles deliver an incomplete set of viral genes to the cell, and therefore cannot support a full cycle of replication unless complemented through co-infection. In addition to SI particles, IAV populations often contain defective-interfering (DI) particles, which actively interfere with production of infectious progeny. With the aim of understanding the significance to viral evolution of these incomplete particles, we tested the hypothesis that SI and DI particles promote diversification through reassortment. Our approach combined computational simulations with experimental determination of infection, co-infection and reassortment levels following co-inoculation of cultured cells with two distinct influenza A/Panama/2007/99 (H3N2)-based viruses. Computational results predicted enhanced reassortment at a given % infection or multiplicity of infection with increasing semi-infectious particle content. Comparison of experimental data to the model indicated that the likelihood that a given segment is missing varies among the segments and that most particles fail to deliver ≥1 segment. To verify the prediction that SI particles augment reassortment, we performed co-infections using viruses exposed to low dose UV. As expected, the introduction of semi-infectious particles with UV-induced lesions enhanced reassortment. In contrast to SI particles, inclusion of DI particles in modeled virus populations could not account for observed reassortment outcomes. DI particles were furthermore found experimentally to suppress detectable reassortment, relative to that seen with standard virus stocks, most likely by interfering with production of infectious progeny from co-infected cells. These data indicate that semi-infectious particles increase the rate of reassortment and may therefore accelerate adaptive evolution of IAV. Since the genome of an influenza A virus has eight non-contiguous segments, two influenza A viruses can exchange genes readily when they infect the same cell. This process of reassortment is important to the evolution of the virus and is one reason why this pathogen is constantly changing. It has long been known that a large proportion of the virus particles that influenza and many other RNA viruses produce are not fully infectious, but the biological significance of these particles has remained unclear. Here we show that virus particles that deliver incomplete genomes to the cell enhance the rate of reassortment. Thus, despite their limited potential to produce progeny viruses, these incomplete particles may play an important role in viral evolution.