Mode of action of ribavirin: Effect of nucleotide pool alterations on influenza virus ribonucleoprotein synthesis

Wray, S K; Gilbert, Brian E.; Noall, Matthew W.; Knight, Vernon

doi:10.1016/0166-3542(85)90012-9

Cited by 118 publications

(90 citation statements)

References 17 publications

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“…Ribavirin's lethal mutagenesis of poliovirus is probably enhanced by the well-characterized ability of ribavirin monophosphate to inhibit the cellular enzyme inosine monophosphate dehydrogenase (IMPDH) and thereby decrease cellular GTP pools (46)(47)(48). The decrease in cellular GTP pools likely increases the frequency of ribavirin incorporation as a mutagenic GTP analog.…”

Section: Discussionmentioning

confidence: 99%

RNA virus error catastrophe: Direct molecular test by using ribavirin

Crotty

Cameron

Andino

2001

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

780

713

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RNA viruses evolve rapidly. One source of this ability to rapidly change is the apparently high mutation frequency in RNA virus populations. A high mutation frequency is a central tenet of the quasispecies theory. A corollary of the quasispecies theory postulates that, given their high mutation frequency, animal RNA viruses may be susceptible to error catastrophe, where they undergo a sharp drop in viability after a modest increase in mutation frequency. We recently showed that the important broad-spectrum antiviral drug ribavirin (currently used to treat hepatitis C virus infections, among others) is an RNA virus mutagen, and we proposed that ribavirin's antiviral effect is by forcing RNA viruses into error catastrophe. However, a direct demonstration of error catastrophe has not been made for ribavirin or any RNA virus mutagen. Here we describe a direct demonstration of error catastrophe by using ribavirin as the mutagen and poliovirus as a model RNA virus. We demonstrate that ribavirin's antiviral activity is exerted directly through lethal mutagenesis of the viral genetic material. A 99.3% loss in viral genome infectivity is observed after a single round of virus infection in ribavirin concentrations sufficient to cause a 9.7-fold increase in mutagenesis. Compiling data on both the mutation levels and the specific infectivities of poliovirus genomes produced in the presence of ribavirin, we have constructed a graph of error catastrophe showing that normal poliovirus indeed exists at the edge of viability. These data suggest that RNA virus mutagens may represent a promising new class of antiviral drugs.

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Section: Discussionmentioning

confidence: 99%

RNA virus error catastrophe: Direct molecular test by using ribavirin

Crotty

Cameron

Andino

2001

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

780

713

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“…Because it is well known that RBV treatment causes GTP‐depletion through IMPDH inhibition,19 we next investigated whether GTP‐depletion by RBV is involved in the suppression of lipogenic genes. For this purpose, OR6Ac cells were treated with RBV and guanosine to replenish GTP pools through the salvage pathway.…”

Section: Resultsmentioning

confidence: 99%

Ribavirin suppresses hepatic lipogenesis through inosine monophosphate dehydrogenase inhibition: Involvement of adenosine monophosphate‐activated protein kinase‐related kinases and retinoid X receptor α

Satoh

Mori

Onomura

et al. 2017

Hepatology Communications

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Ribavirin (RBV) has been widely used as an antiviral reagent, specifically for patients with chronic hepatitis C. We previously demonstrated that adenosine kinase, which monophosphorylates RBV into the metabolically active form, is a key determinant for RBV sensitivity against hepatitis C virus RNA replication. However, the precise mechanism of RBV action and whether RBV affects cellular metabolism remain unclear. Analysis of liver gene expression profiles obtained from patients with advanced chronic hepatitis C treated with the combination of pegylated interferon and RBV showed that the adenosine kinase expression level tends to be lower in patients who are overweight and significantly decreases with progression to advanced fibrosis stages. In our effort to investigate whether RBV affects cellular metabolism, we found that RBV treatment under clinically achievable concentrations suppressed lipogenesis in hepatic cells. In this process, guanosine triphosphate depletion through inosine monophosphate dehydrogenase inhibition by RBV and adenosine monophosphate‐activated protein kinase‐related kinases, especially microtubule affinity regulating kinase 4, were required. In addition, RBV treatment led to the down‐regulation of retinoid X receptor α (RXRα), a key nuclear receptor in various metabolic processes, including lipogenesis. Moreover, we found that guanosine triphosphate depletion in cells induced the down‐regulation of RXRα, which was mediated by microtubule affinity regulating kinase 4. Overexpression of RXRα attenuated the RBV action for suppression of lipogenic genes and intracellular neutral lipids, suggesting that down‐regulation of RXRα was required for the suppression of lipogenesis in RBV action. Conclusion: We provide novel insights about RBV action in lipogenesis and its mechanisms involving inosine monophosphate dehydrogenase inhibition, adenosine monophosphate‐activated protein kinase‐related kinases, and down‐regulation of RXRα. RBV may be a potential reagent for anticancer therapy against the active lipogenesis involved in hepatocarcinogenesis. (Hepatology Communications 2017;1:550–563)

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“…To determine if ribavirin exerts a cytotoxic effect on SHK-1 cells, the CC 50 was estimated. Figure 1B shows that the CC 50 of ribavirin on SHK-1 cells was 9 mg/ml.…”

Section: Resultsmentioning

confidence: 99%

“…Ribavirin has proven to be an inhibitor of several ortho-and paramyxoviruses (42). Furthermore, ribavirin inhibits in vitro and in vivo replication of influenza virus (15,33,49,50), the most typical member of the Orthomyxoviridae family.…”

mentioning

confidence: 99%

“…Ribavirin can be incorporated into nascent genomic RNA, causing an early termination of RNA synthesis or an error catastrophe through the misincorporation of cytidine and uridine instead of guanidine or adenine, which results in lethal mutagenesis (11,47). Ribavirin also inhibits HIV (35,40), vesicular stomatitis virus (VSV) (16), and La Crosse virus (7) polymerase; reovirus transcriptase (36); vaccinia virus guanylyltransferase (19); and influenza virus polymerase (15,50).…”

mentioning

confidence: 99%

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Inhibitory Effect of a Nucleotide Analog on Infectious Salmon Anemia Virus Infection

Rivas‐Aravena

Vallejos‐Vidal²,

Martı́n

et al. 2011

J Virol

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The infectious salmon anemia virus (ISAV), which belongs to the Orthomyxoviridae family, has been responsible for major losses in the salmon industry, with mortalities close to 100% in areas where Atlantic salmon (Salmo salar) is grown. This work studied the effect of ribavirin (1-␤-D-ribofuranosyl-1,2,3-triazole-3-carbaxaide), a broad-spectrum antiviral compound with proven ability to inhibit the replicative cycle of the DNA and RNA viruses. The results show that ribavirin was able to inhibit the infectivity of ISAV in in vitro assays. In these assays, a significant inhibition of the replicative viral cycle was observed with a 50% inhibitory concentration (IC 50 ) of 0.02 g/ml and an IC 90 of 0.4 g/ml of ribavirin. After ribavirin treatment, viral proteins were not detectable and a reduction of viral mRNA association with ribosomes was observed. Ribavirin does not affect the levels of EF1a, nor its association with polysomes, suggesting that the inhibition of RNA synthesis occurs specifically for the virus mRNAs and not for cellular mRNAs. Moreover, ribavirin caused a significant reduction in genomic and viral RNA messenger levels. The study of the inhibitory mechanism showed that it was not reversed by the addition of guanosine. Furthermore, in vivo assays showed a reduction in the mortality of Salmo salar by more than 90% in fish infected with ISAV and treated with ribavirin without adverse effects. In fact, these results show that ribavirin is an antiviral that could be used to prevent ISAV replication either in vitro or in vivo.

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Mode of action of ribavirin: Effect of nucleotide pool alterations on influenza virus ribonucleoprotein synthesis

Cited by 118 publications

References 17 publications

RNA virus error catastrophe: Direct molecular test by using ribavirin

RNA virus error catastrophe: Direct molecular test by using ribavirin

Ribavirin suppresses hepatic lipogenesis through inosine monophosphate dehydrogenase inhibition: Involvement of adenosine monophosphate‐activated protein kinase‐related kinases and retinoid X receptor α

Inhibitory Effect of a Nucleotide Analog on Infectious Salmon Anemia Virus Infection

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