Increased fidelity reduces poliovirus fitness and virulence under selective pressure in mice.
Increased fidelity reduces poliovirus fitness and virulence under selective pressure in mice.
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DOI：
10.1371/journal.ppat.0010011
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发表时间：
2005-10
期刊：
影响因子：
6.7
通讯作者：
Kirkegaard K
中科院分区：
文献类型：
--
作者：
Pfeiffer JK;Kirkegaard K
RNA病毒具有很高的错误率，由此产生的准种可能有助于病毒种群在存在选择压力的情况下生存。因此，有人推测RNA病毒需要高错误率才能生存，而保真度高的病毒应对复杂环境的能力较差。我们之前分离并鉴定了病毒聚合酶 3D-G64S 发生突变的脊髓灰质炎病毒，该病毒通过增加保真度而赋予对诱变核苷酸类似物的抗性。 3D-G64S 病毒在脊髓灰质炎病毒受体转基因小鼠中的致病性低于野生型病毒，尽管在组织培养中仅观察到轻微的生长缺陷。为了确定 3D-G64S 病毒的高保真表型是否会在确定的选择压力下降低其适应性，我们在可逆减毒点突变 2C-F28S 的背景下比较了 3D-G64S 病毒和 3D 野生型病毒的生长。即使具有10倍的输入优势，3D-G64S病毒在可逆减毒突变的背景下也无法与3D野生型病毒竞争；然而，在2C-F28S减毒突变的不可逆版本的背景下，3D-G64S病毒与3D野生型病毒的复制相匹配。因此，3D-G64S高保真表型在确定的选择压力下降低了病毒适应性，这使得小鼠组织中传播的减少可能是由病毒聚合酶保真度的增加引起的。 RNA 病毒在自然界中具有最高的错误率，导致每种病毒可能因一个或多个突变而与群体中的其他病毒不同。这种“不忠”的后果是，整个病毒群体在免疫系统或抗病毒药物的选择性压力下，可能会受益于其一小部分成员的适应性变化。因此，有理论认为RNA病毒需要高错误率才能在复杂的环境中生存。我们使用一种耐药性脊髓灰质炎病毒测试了这一假设，该病毒的聚合酶中含有一个突变，可以减少复制过程中的错误。我们发现，这种高保真突变病毒会降低小鼠的生长速度，小鼠是一个复杂的环境，在受感染的动物体内生长和传播可能需要突变。这种减弱至少部分可能是由于这种突变病毒的高保真度，因为它无法在确定的选择压力的背景下与病毒的低保真度版本竞争。因此，突变可能确实有利于病毒种群，特别是在复杂的环境中，例如受感染的动物或人类。
RNA viruses have high error rates, and the resulting quasispecies may aid survival of the virus population in the presence of selective pressure. Therefore, it has been theorized that RNA viruses require high error rates for survival, and that a virus with high fidelity would be less able to cope in complex environments. We previously isolated and characterized poliovirus with a mutation in the viral polymerase, 3D-G64S, which confers resistance to mutagenic nucleotide analogs via increased fidelity. The 3D-G64S virus was less pathogenic than wild-type virus in poliovirus-receptor transgenic mice, even though only slight growth defects were observed in tissue culture. To determine whether the high-fidelity phenotype of the 3D-G64S virus could decrease its fitness under a defined selective pressure, we compared growth of the 3D-G64S virus and 3D wild-type virus in the context of a revertible attenuating point mutation, 2C-F28S. Even with a 10-fold input advantage, the 3D-G64S virus was unable to compete with 3D wild-type virus in the context of the revertible attenuating mutation; however, in the context of a non-revertible version of the 2C-F28S attenuating mutation, 3D-G64S virus matched the replication of 3D wild-type virus. Therefore, the 3D-G64S high-fidelity phenotype reduced viral fitness under a defined selective pressure, making it likely that the reduced spread in murine tissue could be caused by the increased fidelity of the viral polymerase. RNA viruses have the highest error rates in nature, resulting in the likelihood that each virus differs from other viruses in the population by one or more mutations. The consequence of this “infidelity” is that the viral population as a whole, under selective pressure from the immune system or antiviral drugs, may benefit from adaptive changes in a subset of its members. Therefore, it has been theorized that RNA viruses need high error rates to survive in complex environments. We tested this hypothesis using a drug-resistant poliovirus that contains a mutation in its polymerase that reduces errors during replication. We found that this high-fidelity mutant virus has reduced growth in mice, a complex environment where mutations may be required for growth and spread within the infected animal. At least part of this attenuation is likely due to the high fidelity of this mutant virus, since it was unable to compete with the low-fidelity version of the virus in the context of a defined selective pressure. Therefore, it is likely that mutations do benefit viral populations, especially in complex environments such as an infected animal or human.
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