Avoiding error catastrophe with recombination

RNA recombinationRNA viruses exist close to their error threshold, the point beyond which additional mutations cause loss of infectivity. It has been suggested that RNA recombination prevents viruses from exceeding the error threshold – a situation called error catastrophe – but there has been little experimental support for this hypothesis. An analysis of poliovirus RNA synthesis suggests that this hypothesis is correct.

Error catastrophe has been demonstrated experimentally by treating poliovirus-infected cells with the mutagen ribavirin. Treatment with a concentration of ribavirin that causes a 9.7-fold increase in mutagenesis lead to a 99.3% loss in poliovirus infectivity. The introduction of 2 mutations per genome reduces infectivity to about 30% of wild type RNA, while infectivity is nearly eliminated with 7 mutations per genome.

Ribavirin pushes poliovirus beyond the error threshold because it causes the RNA polymerase to make more errors. A poliovirus mutant resistant to ribavirin has a single amino acid change, G64S, in the viral RNA-dependent RNA polymerase. This ribavirin-resistant enzyme makes fewer errors, and hence is resistant to error catastrophe. The amino acid change is located on the polymerase molecule near the channel where NTPs enter the active site.

A second amino acid change in the poliovirus RNA polymerase, L420A, has been identified that decreases RNA recombination. This process involves the production of genomes with sequences from more than one virus. It occurs when the RNA polymerase copying a viral RNA moves to copy the RNA of another virus (illustrated). RNA recombination is thought to counter error catastrophe because it facilitates the construction of genomes without lethal mutations.

The presence of L420A makes poliovirus more sensitive to ribavirin, consistent with a role for RNA recombination in countering error catastrophe. A virus with both L420A and G64S is just as sensitive to ribavirin – without recombination, even the errors made by a high fidelity polymerase are lethal. A conclusion from these results is that recombination counteracts error catastrophe.

Curiously, poliovirus with the L420A amino acid change alone has no growth defect in HeLa cells, despite the reduced rates of recombination. This observation might be a consequence of the highly permissive nature of HeLa cells, in which mutations have less of an effect. It will be interesting to see if poliovirus with L420A has a growth defect in animals.

I wonder how general is the observation that RNA recombination counteracts error catastrophe. As L420 is conserved among picornaviruses (the virus family including poliovirus), I suspect similar findings will apply to other members of this family. What about other positive strand RNA viruses like flaviviruses, caliciviruses, and coronaviruses? RNA recombination is negligible among negative strand RNA viruses, suggesting that these viruses might exist farther below the error threshold than picornaviruses.

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