An Antiviral Mechanism Investigated with Ribavirin as an RNA Virus Mutagen for Foot-and-mouth Disease Virus

Gu, Chao; Zheng, Cong; Zhang, Qian; Shi, Li; Li, Yong; Qu, S.

doi:10.5483/bmbrep.2006.39.1.009

Cited by 17 publications

(17 citation statements)

References 68 publications

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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).…”

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confidence: 66%

“…Indeed, the doses used in vitro were generally near toxic (50 to 1,000 M, doses that cannot be achieved intracellularly during human therapy), and mutagenesis appeared to be concentration dependent. Interestingly, the ribavirin concentration required to achieve a significant antiviral effect differed between HCV-unrelated viruses (100 to 1,000 M), GB virus B (100 to 200 M), and subgenomic HCV replicons (50 to 400 M) (1,5,8,16,20,21,48). Different cell types might have different capacities to convert ribavirin into RTP, and different rates of division (primary hepatocytes versus cultured cells) could influence the size of the intracellular GTP pool and the affinity of the polymerase for ribavirin.…”

Section: Discussionmentioning

confidence: 99%

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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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confidence: 66%

Section: Discussionmentioning

confidence: 99%

Analysis of Ribavirin Mutagenicity in Human Hepatitis C Virus Infection

Chevaliez

Brillet

Lázaro

et al. 2007

J Virol

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“…At present, ribavirin and pleconaril have been used for treatment of EV71 infection [15][16][17]. Ribavirin, which is a nucleoside analog antiviral drug, exerts antiviral activity against a wide range of DNA and RNA viruses, such as respiratory syncytial virus, herpesvirus, HIV, Lassa fever virus, and hepatitis C virus [18][19][20]. Ribavirin also inhibits EV71 replication in infected cells (IC 50 65-717.98 lg/mL) and prevents virus-induced CPE, reduced mortality and morbidity in infected mice [15,21,22].…”

Section: Introductionmentioning

confidence: 99%

In vitro and in vivo evaluation of ribavirin and pleconaril antiviral activity against enterovirus 71 infection

Zhang

Feng

et al. 2012

Arch Virol

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Enterovirus 71(EV71) causes recurring outbreaks of hand, foot and mouth disease and encephalitis leading to complications or death in young children. More effective antiviral drugs are needed to prevent or reduce EV71-related disease and complications. However, there are no standard models currently in use to evaluate activity against EV71 infection both in vitro and in vivo. In this study, the activity of ribavirin and pleconaril against EV71 infection was evaluated in two models. An in vitro EV71 infection model was developed in RD cells, and an in vivo EV71 infection model was applied. Ribavirin and pleconaril effectively increased the viability of infected cells. Pleconaril reduced the morbidity and mortality of one-day-old infected mice, but ribavirin did not protect the infected mice. In all, the results demonstrated that infected cells and infected mice can be used to evaluate antiviral activity of ribavirin and pleconaril against EV71 infection in vitro and in vivo.

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“…Ribavirin is phosphorylated by cellular adenosine kinase into ribavirin mono-, di-, and triphosphate (RMP, RDP and RTP, respectively) and exhibits its antiviral effect via direct and indirect mechanisms (Gu et al, 2006). RMP affects viral protein synthesis and limits replication of genome and RTP inhibits directly some viral RNA-dependent RNA polymerase activity (Gu et al, 2006). It acts at a stage in the influenza-infected cell, possibly by inhibiting the production of essential nucleotides and hence RNA synthesis.…”

Section: Discussionmentioning

confidence: 99%

“…PEF did not show significant antiviral activity when treated after virus adsorption/fusion, whereas ribavirin exhibited its excellent antiviral effect under this condition. Ribavirin is phosphorylated by cellular adenosine kinase into ribavirin mono-, di-, and triphosphate (RMP, RDP and RTP, respectively) and exhibits its antiviral effect via direct and indirect mechanisms (Gu et al, 2006). RMP affects viral protein synthesis and limits replication of genome and RTP inhibits directly some viral RNA-dependent RNA polymerase activity (Gu et al, 2006).…”

Section: Discussionmentioning

confidence: 99%