2003
DOI: 10.1073/pnas.1232294100
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A single mutation in poliovirus RNA-dependent RNA polymerase confers resistance to mutagenic nucleotide analogs via increased fidelity

Abstract: Ribavirin is a nucleotide analog that can be incorporated by viral polymerases, causing mutations by allowing base mismatches. It is currently used therapeutically as an antiviral drug during hepatitis C virus infections. During the amplification of poliovirus genomic RNA or hepatitis C replicons, error frequency is known to increase upon ribavirin treatment. This observation has led to the hypothesis that ribavirin's antiviral activity results from error catastrophe caused by increased mutagenesis of viral ge… Show more

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Cited by 384 publications
(478 citation statements)
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“…2A), consistent with the lower rate of RNA catalysis associated with a G64S mutation (28). The G64S mutation was stably maintained in virus populations, consistent with previous studies (25)(26)(27); however, the G64S mutation had no effect on the lengths of poly(A) tails in virion RNA (Table 1), as described in further detail below. The G64T and G64D mutations, which were associated with defects in capsid polyprotein processing (see Fig.…”
Section: Resultssupporting
confidence: 88%
See 1 more Smart Citation
“…2A), consistent with the lower rate of RNA catalysis associated with a G64S mutation (28). The G64S mutation was stably maintained in virus populations, consistent with previous studies (25)(26)(27); however, the G64S mutation had no effect on the lengths of poly(A) tails in virion RNA (Table 1), as described in further detail below. The G64T and G64D mutations, which were associated with defects in capsid polyprotein processing (see Fig.…”
Section: Resultssupporting
confidence: 88%
“…The fidelity of RNA replication is reported to influence the quasispecies diversity and the pathogenesis of poliovirus infections (27). A G64S mutation in 3D pol renders poliovirus resistant to ribavirin (25), increases the fidelity of RNA replication (26), and attenuates poliovirus replication in mice (26,27,31). Similar fidelity effects are also seen for a K359R mutation that subtly alters a key charged residue that contacts and helps to position the gamma phosphate of the incoming NTP (47).…”
Section: Discussionmentioning
confidence: 91%
“…Only one amino acid residue substitution (G64S) was previously identified in poliovirus which conferred resistance to ribavirin and decreased quasispecies diversity (Pfeiffer & Kirkegaard, 2003;Vignuzzi et al, 2006). In this study, two different amino acid substitutions were identified, each from a different PRRSV strain, which also occurred in some other RNA viruses.…”
mentioning
confidence: 67%
“…JX044140) and strain MN184B (GenBank accession no. DQ176020), were consecutively passaged each in MARC-145 cells under the selection of ribavirin, which has been successfully used to screen high fidelity virus mutants in vitro by increasing the mutation frequency of RNA viruses above the point of error catastrophe, ultimately driving quasispecies with low fidelity RdRp into extinction (Crotty et al, 2000;Pfeiffer & Kirkegaard, 2003;Sadeghipour et al, 2013;Zeng et al, 2014).…”
mentioning
confidence: 99%
“…It has been suggested that the unusually low substitution rate of hepatitis A virus is due to its having evolved a significantly lower mutation rate than other picornaviruses (6). Indeed, the enterovirus poliovirus has a very high mutation rate that can be lowered through mutations in the RdRp (53,67), indicating that its mutation rate is evolvable. On the other hand, atypical substitution rates within the family have also been attributed to tissue tropism (48).…”
mentioning
confidence: 99%