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viruses have evolved to exist on the edge of error catastrophe due to the advantages conferred by increased adaptability in a complex biological environment. The reduction in the quasispecies nature of the virus population that would be conferred by increased delity could impact the ability of the virus to adapt to the immune response or clinical treatment and even hinder transmission across species barriers. Thus, even though resistance may arise, its ultimate effect may be to reduce pathogenicity through attenuation or the inability to replicate ef ciently in vivo.
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Lethal mutagenesis has not rmly been established as an effective clinical antiviral therapy. This situation is partially due to the fact that the majority of known mutagenic nucleosides exhibit pronounced cellular toxicity, and the corresponding nucleotides would need to be present at high enough intracellular levels to be incorporated at a signi cant frequency during RNA genome replication. Thus, ribavirin is the only antiviral in clinical use which has been hypothesized to possibly exert its effects via lethal mutagenesis. Ribavirin is effective against a broad range of both RNA and DNA viruses in vitro. It is approved for clinical treatment of HCV infection when administered in combination with interferon-a. It is also approved for use against respiratory syncitial virus infection in children, in which case it is administered as an aerosol, and as a treatment for Lassa virus infection. Ribavirin has shown some activity both in vivo and in vitro against hemorrhagic fever viruses, particularly members of the Arenaviridae and Bunyaviridae families,34,35 but ribavirin has no apparent clinical ef cacy against viral hemorrhagic fever induced by loviruses or aviviruses. Ribavirin has also been used to treat infection by Nipah virus,36 Hantavirus,37 and other emerging diseases. Little data exist to strongly support any mechanism of action of ribavirin in clinical cases, and the actual effect of ribavirin on infections in human patients is still under debate. A number of factors have complicated the efforts to detect lethal mutagenesis in clinical samples, including the transient nature of lethally mutated RNA genomes, limitations in detection technology and sample collection, and the possibility of clinical virus populations rapidly acquiring resistance. Monitoring antiviral therapy by reverse transcription-polymerase chain reaction adds the complication that this technology cannot distinguish lethally mutated, unviable genomes from infectious, viable genomes. Thus, conclusions drawn from this data can be misleading. Additionally, current drug delivery methods may not allow suf cient accumulation of lethal mutagens at sites of infection. Clinical doses required to duplicate drug concentrations used in cell culture studies may be toxic or otherwise unattainable. It has been suggested that ribavirin may not accumulate to high enough clinical levels to cause substantial mutagenesis in vivo.23 In many cases, antiviral activity attributed to lethal mutagenesis in vitro or in cell culture has not been duplicated in animal models or in clinical investigations. Although ribavirin presumably acts via lethal mutagenesis when employed against
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GB virus B infection in cultured tamarin hepatocytes, no signi cant antiviral effect was seen in infected tamarins fed ribavirin at high doses.19 However, the recent work by Young and colleagues has provided support for lethal mutagenesis as at least contributing to the effect seen when ribavirin is administered to patients infected with hepatitis C virus.33 A modest mutagenic effect was noted in hepatitis C samples isolated from ribavirin-treated patients. More importantly, the discovery of a speci c mutation in the polymerase of virus isolated from patients treated with ribavirin strongly suggests that the RdRP is the ultimate target of ribavirin therapy in clinical practice. Interestingly, HCV genotype 1a contain a phenylalanine at this position that can be mutated to tyrosine to give resistance, but all other HCV genotypes already contain a consensus tyrosine in this position. Therefore, other genotypes may already be less susceptible to ribavirin treatment. An important consideration in development of mutagenic antivirals as a clinical treatment is the effect on the host. Nucleoside analogues can have considerable toxicity in vivo due to the numerous vital functions nucleosides play in the cell. Nucleotide metabolism is a strictly regulated process, and introduction of an analogue that can inhibit enzymes of these pathways can have quite dramatic effects on cellular viability. Many known nucleoside analogues do in fact act as strong inhibitors of these enzymes.38 Furthermore, conversion of a mutagenic ribonucleoside analogue to the corresponding deoxynucleoside has the potential to cause heritable genetic damage. Ribavirin is not thought to be converted to the deoxynucleoside in any substantial quantities,17 but the structural characteristics responsible for this property are unknown. Ribavirin is a teratogen and interferes with sperm development. It has been suggested that this may be due to incorporation via a cellular RdRP utilized in the cellular RNA interference (RNAi) process.15 All of these possible side effects will need to be considered in the development of lethal mutagens. Recent experiments with SARS-associated coronavirus infection of Vero 76 cells have suggested that ribavirin is ineffective against this virus.39 However, previous work with West Nile virus has shown differences in the ef cacy of ribavirin in cell culture depending on the cell line employed.40 This is likely due to a 13-fold reduction in the accumulation of ribavirin monophosphate in Vero cells.41 Similar results have been obtained in the authors laboratory with poliovirus (J. D. Graci and C. E. Cameron, unpublished data). Ribavirin had only a minimal effect on poliovirus infection of Vero 76 cells as compared to HeLa cells (Figure 9.4). The differences observed between cell types argue that cell culturebased approaches may be insuf cient in determining the potential clinical value of a compound of interest. At the least, results obtained with cultured cells should be viewed with caution unless results can be veri ed with well-characterized cell lines as controls. Importantly, this underscores the fact that the effectiveness of a particular nucleoside analogue is highly dependent on the characteristics of the target cell. Another important discovery has generated signi cant interest in lethal mutagenesis: the realization that cells may have evolved mutagenic activity as an innate
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