Increased Fidelity Reduces Poliovirus Fitness and Virulence under Selective Pressure in Mice

TLDR

RNA viruses rely on high mutation rates to generate quasispecies that can survive selective pressure, suggesting that increased replication fidelity may compromise adaptability. The study aimed to determine whether the high‑fidelity 3D‑G64S poliovirus would exhibit reduced fitness when challenged with a revertible attenuating mutation. The authors compared replication of the 3D‑G64S mutant to wild‑type poliovirus in cell culture and in transgenic mice carrying either a revertible or a non‑revertible 2C‑F28S attenuating mutation. The high‑fidelity virus was less pathogenic in mice, showed only minor growth defects in culture, failed to compete with wild‑type when the 2C‑F28S mutation was revertible, but matched wild‑type replication when the mutation was non‑revertible, demonstrating that increased fidelity diminishes viral fitness under selective pressure.

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.