Curing of foot-and-mouth disease virus from persistently infected cells by ribavirin involves enhanced mutagenesis

Airaksinen, Antero; Pariente, Nonia; Menéndez‐Arias, Luis; Domingo, Esteban

doi:10.1016/s0042-6822(03)00144-2

Cited by 144 publications

(188 citation statements)

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“…These authors reported that ribavirin induced a high frequency of genomic mutations that generated viral progeny with reduced infectivity (7,8). A similar effect of high concentrations of ribavirin has been found in cell cultures infected by RNA viruses belonging to several families, including foot-and-mouth disease virus, Hantaan virus, West Nile virus, and GB virus B, a member of the Flaviviridae family that is closely related to HCV (1,9,16,20,44). In addition, ribavirin has been reported to exert an antiviral effect related to errorprone replication in HCV subgenomic replicons, both in Huh7 cell lines and in a full-length binary HCV replication system (5,20,21,48,53).…”

mentioning

confidence: 58%

Analysis of Ribavirin Mutagenicity in Human Hepatitis C Virus Infection

Chevaliez

Brillet

Lázaro

et al. 2007

J Virol

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The addition of ribavirin to alpha interferon therapy significantly increases response rates for patients with chronic hepatitis C virus (HCV) infection, but ribavirin's antiviral mechanisms are unknown. Ribavirin has been suggested to have mutagenic potential in vitro that would lead to "error catastrophe," i.e., the generation of nonviable viral quasispecies due to the increment in the number of mutant genomes, which prevents the transmission of meaningful genetic information. We used extensive sequence-based analysis of two independent genomic regions in order to test in vivo the hypothesis that ribavirin administration accelerates the accumulation of mutations in the viral genome and that this acceleration occurs only when HCV replication is profoundly inhibited by coadministered alpha interferon. The rate of variation of the consensus sequence, the frequency of mutation, the error generation rate, and the between-sample genetic distance were measured for patients receiving ribavirin monotherapy, a combination of alpha interferon three times per week plus ribavirin, or a combination of alpha interferon daily plus ribavirin. Ribavirin monotherapy did not increase the rate of variation of the consensus sequence, the mutation frequency, the error generation rate, or the betweensample genetic distance. The accumulation of nucleotide substitutions did not accelerate, relative to the pretreatment period, during combination therapy with ribavirin and alpha interferon, even when viral replication was profoundly inhibited by alpha interferon. This study strongly undermines the hypothesis whereby ribavirin acts as an HCV mutagen in vivo.Hepatitis C virus (HCV) infection is a major cause of chronic liver diseases and a global public health problem. Chronic HCV infection affects more than 170 million individuals worldwide, of whom an estimated 20% have or will develop cirrhosis. Furthermore, the annual risk of progression towards hepatocellular carcinoma is 1% to 4% among patients with cirrhosis (36). The combination of pegylated alpha interferon (IFN-␣) and ribavirin is the current standard treatment for chronic HCV infection. This treatment yields a sustained virological response (SVR), defined by the lack of detectable HCV RNA in serum 24 weeks after the end of therapy, in 40 to 50% of patients infected by HCV genotype 1 and in 70% to 80% of patients infected by genotype 2 or 3 (14, 17, 27). The vast majority of patients who have an SVR are cured of the infection.Ribavirin (1-␤-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) is a guanosine analogue with a broad spectrum of activity against DNA and RNA viruses (45). Its use in the treatment of chronic HCV infection has been essentially empirical (36). Indeed, the addition of ribavirin to standard or pegylated IFN-␣ therapy significantly increases the SVR rate over that with IFN monotherapy (14,17,27,30,39) and ribavirin can exert this antiviral effect through several possible mechanisms. HCV clearance is biphasic in responders to 33). The first rapid phase, which occurs...

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mentioning

confidence: 58%

Analysis of Ribavirin Mutagenicity in Human Hepatitis C Virus Infection

Chevaliez

Brillet

Lázaro

et al. 2007

J Virol

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“…The supernatants were extracted with 1,1,2-trichlorotrifluoroethane (Sigma) containing 0.5 M tri-n-octylamine (Sigma), vortexed for 10 s and centrifuged 30 s at 12 000 g. The entire treatment was performed at 0-4 uC, using ice-cold solutions. Nucleotides were separated using a 4.66250 mm Partisil 10 SAX column (Whatman) with a 4.6630 mm Partisil 10 SAX precolumn (Phenomenex), using buffers and elution conditions described by Airaksinen et al (2003). Chromatograms were analysed using the Unicorn 3.00 software (Amersham Pharmacia Biotech).…”

Section: Methodsmentioning

confidence: 99%

An interfering activity against lymphocytic choriomeningitis virus replication associated with enhanced mutagenesis

Martı́n

Abia

Domingo

et al. 2009

Journal of General Virology

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Previous studies have documented that, in the presence of the mutagenic base analogue 5-fluorouracil (FU), lymphocytic choriomeningitis virus (LCMV) that persisted in BHK-21 cells decreased its infectivity to a larger extent than intracellular viral RNA levels, prior to virus extinction. This observation, together with in silico simulations, led to the proposal of the lethal defection model of virus extinction. This model suggests the participation of defective-interfering genomes in the loss of infectivity by increased mutagenesis. Since LCMV naturally produces defective-interfering particles, it was important to show that a capacity to interfere is produced in association with FU treatment. Here, we document that BHK-21 cells persistently infected with LCMV grown in the presence of FU, but not in its absence, generated an interfering activity that suppressed LCMV infectivity. Interference was specific for LCMV and was sensitive to UV irradiation and its activity was dose-and time-dependent. The interfering preparations produced positive LCMV immunofluorescence and viral particles seen by electron microscopy when used to infect cells, despite some preparations being devoid of detectable infectivity. Interference did not involve significant increases of mutant spectrum complexity, as predicted by the lethal defection model. The results provide support for a specific interference associated with LCMV when the virus replicates in the presence of FU. The excess of interference relative to that observed in the absence of FU is necessary for LCMV extinction.

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“…This unique biochemical activity and the high mutation rate of RNA viruses have stimulated the interest in the use of mutagenic rNTP analogs to induce virus entry into error catastrophe. Among them, ribavirin (1-␤-D-ribofuranosyl-1,2,3-triazole-3-carboxamide) and 5-f luorouracil have been shown to drive different RNA viruses to extinction through enhanced mutagenesis, including foot-and-mouth disease virus (FMDV) (4)(5)(6)(7)(8)(9)(10)(11). Structural studies on replicative complexes of viral RDRPs, template-primers, and rNTP substrates or analogs are needed to understand the molecular basis of the low fidelity of copy of these enzymes and the mutagenic activities displayed by rNTP analogs on viral replication.…”

mentioning

confidence: 99%

Sequential structures provide insights into the fidelity of RNA replication

Ferrer-Orta

Arias²,

Pérez-Luque³

et al. 2007

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

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RNA virus replication is an error-prone event caused by the low fidelity of viral RNA-dependent RNA polymerases. Replication fidelity can be decreased further by the use of mutagenic ribonucleoside analogs to a point where viral genetic information can no longer be maintained. For foot-and-mouth disease virus, the antiviral analogs ribavirin and 5-fluorouracil have been shown to be mutagenic, contributing to virus extinction through lethal mutagenesis. Here, we report the x-ray structure of four elongation complexes of foot-and-mouth disease virus polymerase 3D obtained in presence of natural substrates, ATP and UTP, or mutagenic nucleotides, ribavirin triphosphate and 5-fluorouridine triphosphate with different RNAs as template-primer molecules. The ability of these complexes to synthesize RNA in crystals allowed us to capture different successive replication events and to define the critical amino acids involved in (i) the recognition and positioning of the incoming nucleotide or analog; (ii) the positioning of the acceptor base of the template strand; and (iii) the positioning of the 3 -OH group of the primer nucleotide during RNA replication. The structures identify key interactions involved in viral RNA replication and provide insights into the molecular basis of the low fidelity of viral RNA polymerases.5-fluorouracil ͉ foot-and-mouth disease virus ͉ replication fidelity ͉ ribavirin ͉ RNA elongation

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Curing of foot-and-mouth disease virus from persistently infected cells by ribavirin involves enhanced mutagenesis

Cited by 144 publications

References 64 publications

Analysis of Ribavirin Mutagenicity in Human Hepatitis C Virus Infection

Analysis of Ribavirin Mutagenicity in Human Hepatitis C Virus Infection

An interfering activity against lymphocytic choriomeningitis virus replication associated with enhanced mutagenesis

Sequential structures provide insights into the fidelity of RNA replication

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