Genetic studies on the poliovirus 2C protein, an NTPase A plausible mechanism of guanidine effect on the 2C function and evidence for the importance of 2C oligomerization

Tolskaya, Elena A.; Romanova, Lyudmila I.; Kolesnikova, Marina S.; Gmyl, Anatoly P.; Gorbalenya, Alexander E.; Agol, Vadim I.

doi:10.1016/0022-2836(94)90060-4

Cited by 82 publications

(100 citation statements)

References 31 publications

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“…Mutations in most of the noncapsid proteins are unable to be complemented in trans, or if they are, they represent only certain functions of a multifunctional protein (60,61,68). This may result from the formation of the replication complex in cis and from its compact architecture, which sequesters its components and prevents their physical association or exchange with complementing counterparts.…”

Section: Resultsmentioning

confidence: 99%

Formation of the Poliovirus Replication Complex Requires Coupled Viral Translation, Vesicle Production, and Viral RNA Synthesis

Egger

Teterina

Ehrenfeld

et al. 2000

J Virol

152

140

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Section: Resultsmentioning

confidence: 99%

Formation of the Poliovirus Replication Complex Requires Coupled Viral Translation, Vesicle Production, and Viral RNA Synthesis

Egger

Teterina

Ehrenfeld

et al. 2000

J Virol

152

140

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“…Poliovirus resistance to guanidine can be generated by single or multiple point mutations in the 2C coding region (1,(15)(16)(17)(18). By measuring the number of resistant viruses in a population, an estimation of error frequency can be obtained.…”

Section: G64s Poliovirus Displaysmentioning

confidence: 99%

A single mutation in poliovirus RNA-dependent RNA polymerase confers resistance to mutagenic nucleotide analogs via increased fidelity

Pfeiffer

Kirkegaard

2003

Proc. Natl. Acad. Sci. U.S.A.

384

442

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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 genomes. Here, we describe the generation of ribavirin-resistant poliovirus by serial viral passage in the presence of increasing concentrations of the drug. Ribavirin resistance can be caused by a single amino acid change, G64S, in the viral polymerase in an unresolved portion of the fingers domain. Compared with wild-type virus, ribavirinresistant poliovirus displays increased fidelity of RNA synthesis in the absence of ribavirin and increased survival both in the presence of ribavirin and another mutagen, 5-azacytidine. Ribavirin-resistant poliovirus represents an unusual class of viral drug resistance: resistance to a mutagen through increased fidelity.

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“…An N228S change was also found in two fragments (Mut 8 and Mut 11), thus the Mut 8 fragment had three different modifications. In studies on another enterovirus, echovirus 9, it has been found that the substitution A133T conferred resistance to gua-HCl (Klein et al, 2000) and this substitution has been detected in some guanidine-resistant mutants of PV as well (Tolskaya et al, 1994). It seems that the A133T and D160A changes in the SVDV 2C protein are each able to confer resistance to guanidine alone.…”

Section: Characterization Of Guanidine-resistant Svdvmentioning

confidence: 99%

Dynamics of picornavirus RNA replication within infected cells

Belsham

Normann

2008

Journal of General Virology

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Replication of many picornaviruses is inhibited by low concentrations of guanidine. Guanidine-resistant mutants are readily isolated and the mutations map to the coding region for the 2C protein. Using in vitro replication assays it has been determined previously that guanidine blocks the initiation of negative-strand synthesis. We have now examined the dynamics of RNA replication, measured by quantitative RT-PCR, within cells infected with either swine vesicular disease virus (an enterovirus) or foot-and-mouth disease virus as regulated by the presence or absence of guanidine. Following the removal of guanidine from the infected cells, RNA replication occurs after a significant lag phase. This restoration of RNA synthesis requires de novo protein synthesis. Viral RNA can be maintained for at least 72 h within cells in the absence of apparent replication but guanidine-resistant virus can become predominant. Amino acid substitutions within the 2C protein that confer guanidine resistance to swine vesicular disease virus and foot-and-mouth disease virus have been identified. Even when RNA synthesis is well established, the addition of guanidine has a major impact on the level of RNA replication. Thus, the guanidine-sensitive step in RNA synthesis is important throughout the virus life cycle in cells.

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Genetic studies on the poliovirus 2C protein, an NTPase A plausible mechanism of guanidine effect on the 2C function and evidence for the importance of 2C oligomerization

Cited by 82 publications

References 31 publications

Formation of the Poliovirus Replication Complex Requires Coupled Viral Translation, Vesicle Production, and Viral RNA Synthesis

Formation of the Poliovirus Replication Complex Requires Coupled Viral Translation, Vesicle Production, and Viral RNA Synthesis

A single mutation in poliovirus RNA-dependent RNA polymerase confers resistance to mutagenic nucleotide analogs via increased fidelity

Dynamics of picornavirus RNA replication within infected cells

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