The role of genetic diversity of RNA viruses in virulence and pathogenesis
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 ra...
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Información proyecto RNAVIRUSDIVNPATHO
Líder del proyecto
INSTITUT PASTEUR
No se ha especificado una descripción o un objeto social para esta compañía.
TRL
4-5
Presupuesto del proyecto
100K€
Fecha límite de participación
Sin fecha límite de participación.
Descripción del proyecto
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 are shifting 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 and a more realistic evaluation of modulating genetic diversity as a vaccine approach.