LETHAL MUTAGENESIS AS AN ANTIVIRAL STRATEGY in .NET

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LETHAL MUTAGENESIS AS AN ANTIVIRAL STRATEGY
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FIGURE 9.4 Ribavirin has minimal effect on poliovirus in Vero 76 cells. HeLa cells () or Vero 76 cells (&) (1 105) were pretreated with ribavirin for 18 hours, then infected with 2000 PFU PV. Infected cells were incubated in the presence of compound until cell death. Virus was harvested by freeze thaw and titer was determined.
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antiviral defense mechanism. Recently, the enzyme APOBEC3G has been showned to be responsible for the reduced infectivity of vif HIV in nonpermissive cells.42 This enzyme is a DNA-speci c cytidine deaminase, and its expression causes an increase in dC-to-dU mutations in E. coli.43 Currently, it is believed that APOBEC3G is included in virions and, upon entry of HIV into a new host cell, deaminates the rst retroviral negative strand during replication, causing dC-to-dU transistions.44 The resultant increase in mutation frequency should have a deleterious effect on genome stability and delity of replication. This antiviral activity was found to be absent in the presence of Vif. Recent investigations into this property of Vif have suggested that Vif can induce ubiquitination and subsequent degradation of APOBEC3G via cellular proteasomal pathways, therefore preventing its incorporation into virions.45 49 It has also been reported that APOBEC3G expression leads to enhanced degradation of Vif via ubiquitination, suggesting a reciprocal relationship in which both proteins may be degraded in a single complex.49 APOBEC3G is active against other retroviruses44,50 and has also been shown to inhibit hepatitis B virus of the family Hepadnaviridae, although mutagenesis was not detected in this particular study.51 This discovery of a cellular mutagenic antiviral activity raises many important questions. Do cells possess other antiviral activities that can induce mutagenesis of foreign genomes Is such a strategy utilized against other DNA- or RNA-based viruses Clearly, HIV Vif has evolved to suppress this cellular response. But have other viruses acquired similar countermeasures, and can these be exploited for therapeutic approaches Further understanding of this innate antiviral defense mechanism may help in developing lethal mutagenesis as a clinical strategy.
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LETHAL MUTAGENESIS: EXPLOITING ERROR-PRONE REPLICATION OF RIBOVIRUSES
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The ADAR (adenosine deaminase that acts on RNA) family of enzymes has provocative characteristics that may suggest it can target viral RNA genomes for mutation. The enzymes bind to RNA that is highly doubled-stranded and catalyze the conversion of adenosine to inosine, which is generally recognized as guanosine by most enzymes.52 Human ADAR1-L is highly active in the cytoplasm 53 and expressed as part of the interferon response. Whether this enzyme acts as part of an innate antiviral defense mechanism has yet to be thoroughly investigated.
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Recent research has demonstrated the promise of lethal mutagenesis as an antiviral strategy. Exploitation of this strategy to produce broad-spectrum antiviral mutagens has become an exciting possibility. Unfortunately, many of the hurdles to be overcome in translating these discoveries into clinical use are not well understood. In this nal section of the chapter, we provide a brief overview of some challenges to overcome in order to develop lethal mutagenesis into a clinically useful antiviral strategy. Investigation of Known Mutagens as Antivirals and Development of New Nucleoside Analogues. An extensive compendium of information has accumulated on synthetic nucleoside chemistry, and numerous nucleoside analogues have already been synthesized and characterized. In light of recent results with lethal mutagenesis, it may be worthwhile to reevaluate known mutagenic analogues for antiviral activity. In addition, novel nucleoside analogues should be developed in the search for more effective lethal mutagens. Work in this area has already begun.54 56 The goal should be not only to develop mutagenic analogues but also to work toward understanding the molecular charactersitics and structure function relationships underlying incorporation and delity characteristics of nucleoside analogues in the context of viral RdRPs. In addition, further elucidation of the properties required for effective cellular import and phosphorylation, essential for in vitro utilization of mutagenic nucleosides, is required (reviewed previously).14 Understanding the Effect of Lethal Mutagenesis on Different Viruses. As mentioned earlier, coxsackievirus B3 was found to be more susceptible to ribavirin-induced mutagenesis than poliovirus. Thus, even closely related viruses may have widely varying responses to an increase in error frequency. This differential susceptibility may be due either to differences in the delity of the virus polymerases or to increased susceptibility of the genome itself to mutation. However, the biological basis for this is not understood. One possibility is that viruses which must replicate in a variety of different host cells (or in different organisms, as in the vectorborne viruses) may be more constrained in the breadth of sequences that can be tolerated. Understanding the relationship between polymerase delity, constraints on sequence variability, and the effect of
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