Variation in RNA virus mutation rates across host cells

Abstract

It is well established that RNA viruses exhibit higher rates of spontaneous mutation than DNA viruses and microorganisms. However, their mutation rates vary amply, from 10(-6) to 10(-4) substitutions per nucleotide per round of copying (s/n/r) and the causes of this variability remain poorly understood. In addition to differences in intrinsic fidelity or error correction capability, viral mutation rates may be dependent on host factors. Here, we assessed the effect of the cellular environment on the rate of spontaneous mutation of the vesicular stomatitis virus (VSV), which has a broad host range and cell tropism. Luria-Delbrück fluctuation tests and sequencing showed that VSV mutated similarly in baby hamster kidney, murine embryonic fibroblasts, colon cancer, and neuroblastoma cells (approx. 10(-5) s/n/r). Cell immortalization through p53 inactivation and oxygen levels (1-21%) did not have a significant impact on viral replication fidelity. This shows that previously published mutation rates can be considered reliable despite being based on a narrow and artificial set of laboratory conditions. Interestingly, we also found that VSV mutated approximately four times more slowly in various insect cells compared with mammalian cells. This may contribute to explaining the relatively slow evolution of VSV and other arthropod-borne viruses in nature.

Figure 1. VSV mutation rate to the MAR phenotype estimated by the Luria-Delbrück fluctuation test in different cellular environments.

Each dot represents an independent estimate (n = 3 for all except n = 6 for BHK-21 and n = 4 for BHK-21 at 28°C). Horizontal bars indicate the mean rate. Detailed information for each test is provided in Table 1 and in Text S1.

Figure 2. Molecular evolution of directly transmitted and arthropod-transmitted riboviruses.

Data were collected from the supplementary information of a previous meta-analysis and include 170 evolutionary rates, 113 for directly transmitted viruses and 57 for arboviruses. The box plot indicates the median (central lines), percentiles 25/75 (box) and percentiles 10/90 (bars), and outliers (dots).