English   español  
Por favor, use este identificador para citar o enlazar a este item: http://hdl.handle.net/10261/8387
Compartir / Impacto:
Estadísticas
Add this article to your Mendeley library MendeleyBASE
Ver citas en Google académico
Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL
Exportar otros formatos: Exportar EndNote (RIS)Exportar EndNote (RIS)Exportar EndNote (RIS)
Título

Caracterización molecular de la resistencia a ribavirina en el virus de la fiebre aftosa

Autor Sierra García, Macarena
DirectorDomingo, Esteban
Palabras clave Aftovirus
Ribavirina
Fecha de publicación 2007
EditorUniversidad Autónoma de Madrid
ResumenRNA virus populations are complex distributions of closely related but nonidentical variant genomes termed quasispecies. The large heterogeneity in quasispecies is due to the low fidelity of viral RNA polymerases and the lack of error-repair activities during replication. Studies on genome replication with high error rates predict the existence of an error threshold above which the maintenance of the genetic information would not be possible. The quasispecies structure would be lost when the error rate of replication crosses the error threshold, in a process that has been termed entry into error catastrophe. This fact opens interesting possibilities for the design of a new antiviral strategy based on inducing viral error catastrophe by forcing viruses to replicate in the presence of mutagens. The term lethal mutagenesis is referred to as viral extinction through error catastrophe. A critical question for the application of error catastrophe is whether mutations can occur that render viruses resistant to mutagenic agents. The main objective of this Ph. D. Thesis is to understand the mechanisms underlying resistance of RNA viruses to mutagenic agents and the evolutionary implications of quasispecies dynamics. The nucleoside analogue ribavirin (R) is mutagenic for foot-and-mouth disease virus (FMDV). We have selected FMDV with amino acid substitution M296I in the viral polymerase (3D) by passaging FMDV in the presence of increasing concentrations of R. Measurements of progeny production and viral fitness with chimeric viruses in the presence and absence of R documented that 3D substitution M296I conferred FMDV a selective replicative advantage in the presence of R but not in the absence of R. Purified mutant polymerase with I296 showed a decreased capacity to use ribavirin triphosphate (RTP) as substrate as compared with the wild type enzyme. The results suggest that M296I has been selected because it attenuates the mutagenic activity of R on FMDV. Replacement M296I is located within a highly conserved stretch in picornaviral polymerases, which includes residues that interact with template-primer and with the incoming nucleotide, according to the three-dimensional structure of FMDV 3D. Given that a 3D substitution, distant from M296I, was associated with resistance to R in poliovirus, the results indicate that picornaviral polymerases include different sites that can alter the interaction of the enzyme with mutagenic nucleoside analogues. Implications for lethal mutagenesis are discussed.
Descripción Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura 13-07-2007
URI http://hdl.handle.net/10261/8387
Aparece en las colecciones: (CBM) Tesis
Ficheros en este ítem:
Fichero Descripción Tamaño Formato  
Macarena Sierra García.pdf3,2 MBAdobe PDFVista previa
Visualizar/Abrir
Mostrar el registro completo
 


NOTA: Los ítems de Digital.CSIC están protegidos por copyright, con todos los derechos reservados, a menos que se indique lo contrario.