Abstract
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.
Highlights
RNA viruses have the highest replicative error rates in nature, with approximately one mistake made per 1,000– 100,000 nucleotides copied [1,2,3]
We found that 3D-G64S poliovirus is less pathogenic than wild-type virus in mice, but displays little
We argue that, in the face of the myriad selective pressures encountered by poliovirus during murine infection, the decreased variability in the population generated by the relatively highfidelity 3D-G64S polymerase may be a distinct disadvantage for the growth and spread of the mutant virus
Summary
RNA viruses have the highest replicative error rates in nature, with approximately one mistake made per 1,000– 100,000 nucleotides copied [1,2,3]. Viruses with mutations that confer resistance to neutralizing antibodies would benefit the virus population as a whole under selective pressure from the host immune response. The vast majority of errors made during replication are deleterious, resulting in debilitation of a high percentage of the population. RNA viruses live on the edge of ‘‘error catastrophe,’’ where the cost of deleterious mutations is in dynamic balance with the benefit of adaptive mutations [1,5,6]
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