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RNA virus population diversity, virulence, attenuation and vaccine development

Objectif

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 that have been observed for all RNA viruses. Recently, we have developed a model system to study the roles that RNA virus mutation rates and population heterogeneity play in virus fitness, virulence and pathogenesis in vivo. The system relies on altering the RdRp fidelity of poliovirus, thereby changing the amount of genetic diversity present in a population. We found that increasing or decreasing genetic diversity strongly attenuates the virus and may constitute a novel strategy to engineer live virus vaccines. However, the poliovirus infection model of transgenic mice presents significant limitations that do not permit more detailed studies of the mechanisms behind these observations. To further extend our preliminary results, we will develop two new infection models, to study the role of genetic diversity and population dynamics of RNA viruses infecting their hosts naturally. These models will be used to uncover the mechanisms by which genetic diversity is generated, the points in infection when it is critical and the specific bottlenecking events or subpopulations that are involved at these critical points. We will use new deep sequencing technology, coupled to concepts in population genetics, to develop new strategies for vaccine discovery based on the modulation of RNA virus populations.

Appel à propositions

ERC-2009-StG
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Régime de financement

ERC-SG - ERC Starting Grant

Institution d’accueil

INSTITUT PASTEUR
Adresse
Rue Du Docteur Roux 25-28
75724 Paris Cedex 15
France
Type d’activité
Research Organisations
Contribution de l’UE
€ 1 870 000
Chercheur principal
Marco Vignuzzi (Dr.)
Contact administratif
Marie-Laure Rosso (Ms.)

Bénéficiaires (1)

INSTITUT PASTEUR
France
Contribution de l’UE
€ 1 870 000
Adresse
Rue Du Docteur Roux 25-28
75724 Paris Cedex 15
Type d’activité
Research Organisations
Chercheur principal
Marco Vignuzzi (Dr.)
Contact administratif
Marie-Laure Rosso (Ms.)