|Viral Populations and Pathogenesis - CNRS URA 3015|
|HEAD||Dr. Marco VIGNUZZI / firstname.lastname@example.org|
|MEMBERS||Ana DE CASAS, sécretaire Stéphanie BEAUCOURT, technicienne / Marta SANZ RAMOS ROJO, stagiaire / Dr. Lark COFFEY, postdoctorant / Laura LEVY, stagiaire M2
Sequence space and RNA virus quasispecies structures
Our new group is building on observations and in vivo models developed by Vignuzzi et al. to study the behaviour of RNA viruses as populations during the course of an infection. Like any population of organisms, a virus population interacts with, reacts to, influences and is influenced by the environment it inhabits. We are interested in following the population dynamics and fluctuation of an RNA virus population as it enters the “virgin” territory of a new host and is eventually transmitted from this host during infection. When a host is infected, relatively few virus particles form the founding population that replicates, expands and disseminates during systemic infection. This expanding population encounters numerous environmental changes and challenges that include physical/anatomical barriers, tissue specific environments and the innate and adaptive immune responses. The arms race that occurs between virus and host environment influences the population structures that are eventually transmitted to new hosts, either naive or immune. We are hoping to identify the points during infection when the virus population is either most fragmented, most restricted or most heavily challenged by environmental pressure – target points for antiviral approaches.
Polymerase Fidelity and Virus Population Diversity
In recent years, viral RNA dependent RNA polymerases (RdRps) have been isolated with altered fidelity (Pfeiffer and Kirkegaard, 2003; Vignuzzi et al., 2008). High fidelity RdRps of poliovirus were shown to generate restricted quasispecies, virus populations of limited genetic diversity. Although the replication kinetics of these viruses were similar to wild type virus, these populations were compromised in their adaptability and virulence.
We are isolating higher and lower fidelity variants of numerous RNA viruses, belonging to the picornavirus, flavivirus and alphavirus families to determine the range of error rate and mutation frequency tolerated by these viruses and to understand the reasons why a less-than-perfect replication fidelity would be beneficial. These fidelity variants will be used as tools to study population dynamics of viral pathogenesis.
Keywords: quasispecies, polymerase fidelity, RNA virus
1: Vignuzzi M, Wendt E, Andino R. 2008. Engineering attenuated virus vaccines by controlling replication fidelity. Nat Med. 2008 Feb;14(2):154-61. PMID: 18246077
2: Geller R, Vignuzzi M, Andino R, Frydman J. 2007. Evolutionary constraints on chaperone-mediated folding provide an antiviral approach refractory to development of drug resistance. Genes Dev.2007 Jan 15;21(2):195-205. PMID: 17234885
3: Vignuzzi M, Stone JK, Arnold JJ, Cameron CE, Andino R. 2006. Quasispecies diversity determines pathogenesis through cooperative interactions in a viral population. Nature. 2006 Jan 19;439(7074):344-8. Epub 2005 Dec 4. PMID: 16327776
4: Arnold JJ, Vignuzzi M, Stone JK, Andino R, Cameron CE. 2005. Remote site control of an active site fidelity checkpoint in a viral RNA-dependent RNA polymerase. J Biol Chem. 2005 Jul 8;280(27):25706-16. Epub 2005 May 5. PMID: 15878882
5: Vignuzzi M, Stone JK, Andino R. 2005. Ribavirin and lethal mutagenesis of poliovirus: molecular mechanisms, resistance and biological implications. Virus Res. 2005 Feb;107(2):173-81. Review. PMID: 15649563
Activity Reports 2009 - Institut Pasteur
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