Application of Quasispecies Concepts to RNA Virus Attenuation and Vaccine Development – QuasispeciesVax
RNA viruses have the highest mutation frequencies in nature, which are in large part attributed to the low fidelity of their viral RNA-dependent RNA polymerases (RdRp). Explosive replication kinetics coupled with high mutation rates quickly generate highly diverse populations (quasispecies) maintained by mutation-selection balance. RNA virus quasispecies have been observed for nearly all RNA viruses, but whether genetic heterogeneity is a function or consequence of a the virus' interaction with its host environment has been difficult to answer, particularly in vivo. Recently, we have developed a model system to study these questions by altering the RdRp fidelity of poliovirus, thereby changing the amount of genetic diversity present in a population. We showed that viral infectivity, dissemination and pathogenicity were dependent on the level of genetic diversity present within a viral population. We also showed that restricting genetic diversity strongly attenuates virus and may constitute a novel strategy to engineer live virus vaccines. However, the poliovirus model of infection of transgenic mice presents significant differences and limitations with respects to a natural host infection. To further extend our preliminary results, we propose to shift the expertise acquired in these recent studies to a more natural model of infection, using the Coxsackie B3 virus. This new model of study will permit a more detailed determination of the role of genetic diversity in pathogenesis. We will use our new study model to develop new approaches to vaccine discovery based on quasispecies concepts.
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