Insights into RNA Virus Mutant Spectrum and Lethal Mutagenesis Events: Replicative Interference and Complementation by Multiple Point Mutants

2007 ◽  
Vol 369 (4) ◽  
pp. 985-1000 ◽  
Author(s):  
Celia Perales ◽  
Roberto Mateo ◽  
Mauricio G. Mateu ◽  
Esteban Domingo
Keyword(s):  
Rna Virus ◽  
Multiple Point ◽  
Lethal Mutagenesis ◽  
Mutant Spectrum ◽  
Virus Mutant

scholarly journals Extinction of West Nile Virus by Favipiravir through Lethal Mutagenesis

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Estela Escribano-Romero ◽  
Nereida Jiménez de Oya ◽  
Esteban Domingo ◽  
Juan Carlos Saiz
Keyword(s):  
West Nile Virus ◽  
Mutation Frequency ◽  
Ebola Virus ◽  
Rna Viruses ◽  
Lethal Dose ◽  
Antiviral Agent ◽  
West Nile ◽  
Lethal Mutagenesis ◽  
Mutant Spectrum

ABSTRACT Favipiravir is an antiviral agent effective against several RNA viruses. The drug has been shown to protect mice against experimental infection with a lethal dose of West Nile virus (WNV), a mosquito-borne flavivirus responsible for outbreaks of meningitis and encephalitis for which no antiviral therapy has been licensed; however, the mechanism of action of the drug is still not well understood. Here, we describe the potent in vitro antiviral activity of favipiravir against WNV, showing that it decreases virus-specific infectivity and drives the virus to extinction. Two passages of WNV in the presence of 1 mM favipiravir—a concentration that is more than 10-fold lower than its 50% cytotoxic concentration (CC50)—resulted in a significant increase in mutation frequency in the mutant spectrum and in a bias toward A→G and G→A transitions relative to the population passaged in the absence of the drug. These data, together with the fact that the drug is already licensed in Japan against influenza virus and in a clinical trial against Ebola virus, point to favipiravir as a promising antiviral agent to fight medically relevant flaviviral infections, such as that caused by WNV.

scholarly journals Mutational Robustness of an RNA Virus Influences Sensitivity to Lethal Mutagenesis

2011 ◽  
Vol 86 (5) ◽  
pp. 2869-2873 ◽  
Author(s):  
J. D. Graci ◽  
N. F. Gnadig ◽  
J. E. Galarraga ◽  
C. Castro ◽  
M. Vignuzzi ◽  
...  
Keyword(s):  
Rna Virus ◽  
Mutational Robustness ◽  
Lethal Mutagenesis

scholarly journals Lethal Mutagenesis of Poliovirus Mediated by a Mutagenic Pyrimidine Analogue

2007 ◽  
Vol 81 (20) ◽  
pp. 11256-11266 ◽  
Author(s):  
Jason D. Graci ◽  
Daniel A. Harki ◽  
Victoria S. Korneeva ◽  
Jocelyn P. Edathil ◽  
Kathleen Too ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Mechanism Of Action ◽  
Rna Viruses ◽  
Rna Virus ◽  
Virus Titer ◽  
High Fidelity ◽  
Mutational Robustness ◽  
Lethal Mutagenesis ◽  
The Impact

ABSTRACT Lethal mutagenesis is the mechanism of action of ribavirin against poliovirus (PV) and numerous other RNA viruses. However, there is still considerable debate regarding the mechanism of action of ribavirin against a variety of RNA viruses. Here we show by using T7 RNA polymerase-mediated production of PV genomic RNA, PV polymerase-catalyzed primer extension, and cell-free PV synthesis that a pyrimidine ribonucleoside triphosphate analogue (rPTP) with ambiguous base-pairing capacity is an efficient mutagen of the PV genome. The in vitro incorporation properties of rPTP are superior to ribavirin triphosphate. We observed a log-linear relationship between virus titer reduction and the number of rPMP molecules incorporated. A PV genome encoding a high-fidelity polymerase was more sensitive to rPMP incorporation, consistent with diminished mutational robustness of high-fidelity PV. The nucleoside (rP) did not exhibit antiviral activity in cell culture, owing to the inability of rP to be converted to rPMP by cellular nucleotide kinases. rP was also a poor substrate for herpes simplex virus thymidine kinase. The block to nucleoside phosphorylation could be bypassed by treatment with the P nucleobase, which exhibited both antiviral activity and mutagenesis, presumably a reflection of rP nucleotide formation by a nucleotide salvage pathway. These studies provide additional support for lethal mutagenesis as an antiviral strategy, suggest that rPMP prodrugs may be highly efficacious antiviral agents, and provide a new tool to determine the sensitivity of RNA virus genomes to mutagenesis as well as interrogation of the impact of mutational load on the population dynamics of these viruses.

scholarly journals Hidden Virulence Determinants in a Viral Quasispecies In Vivo

2008 ◽  
Vol 82 (21) ◽  
pp. 10465-10476 ◽  
Author(s):  
Marta Sanz-Ramos ◽  
Fayna Díaz-San Segundo ◽  
Cristina Escarmís ◽  
Esteban Domingo ◽  
Noemí Sevilla
Keyword(s):  
Genomic Sequence ◽  
Rna Virus ◽  
Consensus Sequence ◽  
Nucleotide Sequences ◽  
Intermediate Phenotype ◽  
Viral Population ◽  
Virulence Determinants ◽  
Mouth Disease Virus ◽  
Mutant Spectrum

ABSTRACT The characterization of virulence determinants of pathogenic agents is of utmost relevance for the design of disease control strategies. So far, two classes of virulence determinants have been characterized for viral populations: those imprinted in the nucleotide sequence of some specific genomic regions and those that depend on the complexity of the viral population as such. Here we provide evidence of a virulence determinant that depends neither on a genomic sequence nor on detectable differences in population complexity. Foot-and-mouth disease virus is lethal for C57BL/6 mice showing the highest viral load in pancreas. Virus isolated from pancreas after one passage in mice showed an attenuated phenotype, with no lethality even at the highest dose tested. By contrast, virus from sera of the same mice displayed a virulence similar to that of the parental wild-type clone and virus isolated from spleen displayed an intermediate phenotype. However, viral populations from pancreas, spleen, and serum showed indistinguishable consensus genomic nucleotide sequences and mutant spectrum complexities, as quantified according to the mutation frequencies of both entire genomic nucleotide sequences of biological clones. The results show that the populations with differing virulences cannot be distinguished either by the consensus sequence or by the average complexity of the mutant spectrum. Differential harvesting of virus generated by cell transfection of RNA from serum and pancreas failed to reveal genetic differences between subpopulations endowed with differing virulences. In addition to providing evidence of hidden virulence determinants, this study underlines the capacity of a clone of an RNA virus to rapidly diversify phenotypically in vivo.

scholarly journals Molecular intermediates of fitness gain of an RNA virus: characterization of a mutant spectrum by biological and molecular cloning

2001 ◽  
Vol 82 (5) ◽  
pp. 1049-1060 ◽  
Author(s):  
Armando Arias ◽  
Ester Lázaro ◽  
Cristina Escarmís ◽  
Esteban Domingo
Keyword(s):  
Molecular Cloning ◽  
Rna Virus ◽  
Foot And Mouth Disease ◽  
Nucleotide Sequencing ◽  
Coding Region ◽  
Entry Site ◽  
Mouth Disease Virus ◽  
Mutant Spectrum ◽  
Genomic Regions

The mutant spectrum of a virus quasispecies in the process of fitness gain of a debilitated foot-and-mouth disease virus (FMDV) clone has been analysed. The mutant spectrum was characterized by nucleotide sequencing of three virus genomic regions (internal ribosome entry site; region between the two AUG initiation codons; VP1-coding region) from 70 biological clones (virus from individual plaques formed on BHK-21 cell monolayers) and 70 molecular clones (RT–PCR products cloned in E. coli). The biological and molecular clones provided statistically indistinguishable definitions of the mutant spectrum with regard to the distribution of mutations among the three genomic regions analysed and with regard to the types of mutations, mutational hot-spots and mutation frequencies. Therefore, the molecular cloning procedure employed provides a simple protocol for the characterization of mutant spectra of viruses that do not grow in cell culture. The number of mutations found repeated among the clones analysed was higher than expected from the mean mutation frequencies. Some components of the mutant spectrum reflected genomes that were dominant in the prior evolutionary history of the virus (previous passages), confirming the presence of memory genomes in virus quasispecies. Other components of the mutant spectrum were genomes that became dominant at a later stage of evolution, suggesting a predictive value of mutant spectrum analysis with regard to the outcome of virus evolution. The results underline the observation that greater insight into evolutionary processes of viruses may be gained from detailed clonal analyses of the mutant swarms at the sequence level.

scholarly journals A REVIEW ON THE STATE OF ZIKA VIRUS IN NIGERIA

2019 ◽  
Vol 6 (1) ◽  
Author(s):  
Akeeb O .bola Oyefolu ◽  
Joseph Ojonugwa Shaibu ◽  
Abdul-azeez A. Anjorin ◽  
Kabiru O. Akinyemi
Keyword(s):  
Zika Virus ◽  
Environmental Changes ◽  
Rna Virus ◽  
The State ◽  
Original Research ◽  
Virus Infections ◽  
African Countries ◽  
Current State ◽  
First Case ◽  
Virus Mutant

Background: Zika virus, a flavivirus primarily transmitted through bites of mosquito (Aedes aegypti), blood transfusion, sexual contact and motherto-child was named after Zika forest in Uganda where it was first isolated from a sentinel monkey in 1947. It is a positively sensed single stranded RNA virus (+ssRNA) of approximately 11000Kb in length, encoding three (3) structural and seven (7) non-structural proteins. The virus has spread across several countries of the world between 1947 and today. Between March 2015 and November 2016, about 500,000 to 1.5 million people have been reported infected with Zika virus in Brazil alone, resulting in several cases of microcephaly, severe brain and ocular malformations, abortions, Guillain-Barre syndrome and even deaths. Cases of Zika virus infections have also been documented in some African countries with resulting isolation and sequencing of several strains. In Nigeria however, the first case of Zika virus was reported as far back as 1954 in the Eastern part of the country during a research on Yellow fever. Zika virus mutant strains might have evolved with corresponding effects on man due to continuous environmental changes and human factors worldwide. Aim: This study was aimed at reviewing the state of Zika virus in Nigeria: past and present. Methods: Original research articles and reviews were searched on the NCBI, Research gate, PubMed and Google scholar using queries such as; Zika, epidemiology of Zika, pathogenesis of Zika and molecular characterization of Zika. Results: High points on virology, epidemiology, pathogenesis, diagnosis, prevention and management were pooled together and discussed. Conclusion: The knowledge gained from this paper will help understand the current state of Zika virus in Nigeria. Keywords: Nigeria, Zika, flavivirus, RNA, microcephaly, epidemiology, genomics.

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