scholarly journals Rare haplotype load as marker for lethal mutagenesis

PLoS ONE ◽  
2018 ◽  
Vol 13 (10) ◽  
pp. e0204877 ◽  
Author(s):  
Josep Gregori ◽  
María Eugenia Soria ◽  
Isabel Gallego ◽  
Mercedes Guerrero-Murillo ◽  
Juan Ignacio Esteban ◽  
...  
Keyword(s):  
Rare Haplotype ◽  
Lethal Mutagenesis

scholarly journals Two-dimensional IR spectroscopy of the anti-HIV agent KP1212 reveals protonated and neutral tautomers that influence pH-dependent mutagenicity

2015 ◽  
Vol 112 (11) ◽  
pp. 3229-3234 ◽  
Author(s):  
Chunte Sam Peng ◽  
Bogdan I. Fedeles ◽  
Vipender Singh ◽  
Deyu Li ◽  
Tiffany Amariuta ◽  
...  
Keyword(s):  
Ir Spectroscopy ◽  
Mutation Rates ◽  
Viral Population ◽  
Lethal Mutagenesis ◽  
2D Ir ◽  
Viral Mutation ◽  
Unique Shape ◽  
Ph Dependent ◽  
Mutagenic Property ◽  
Anti Hiv

Antiviral drugs designed to accelerate viral mutation rates can drive a viral population to extinction in a process called lethal mutagenesis. One such molecule is 5,6-dihydro-5-aza-2′-deoxycytidine (KP1212), a selective mutagen that induces A-to-G and G-to-A mutations in the genome of replicating HIV. The mutagenic property of KP1212 was hypothesized to originate from its amino–imino tautomerism, which would explain its ability to base pair with either G or A. To test the multiple tautomer hypothesis, we used 2D IR spectroscopy, which offers subpicosecond time resolution and structural sensitivity to distinguish among rapidly interconverting tautomers. We identified several KP1212 tautomers and found that >60% of neutral KP1212 is present in the enol–imino form. The abundant proportion of this traditionally rare tautomer offers a compelling structure-based mechanism for pairing with adenine. Additionally, the pKa of KP1212 was measured to be 7.0, meaning a substantial population of KP1212 is protonated at physiological pH. Furthermore, the mutagenicity of KP1212 was found to increase dramatically at pH <7, suggesting a significant biological role for the protonated KP1212 molecules. Overall, our data reveal that the bimodal mutagenic properties of KP1212 result from its unique shape shifting ability that utilizes both tautomerization and protonation.

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 Lethal mutagenesis of Rift Valley fever virus induced by favipiravir

2019 ◽  
Author(s):  
Belén Borrego ◽  
Ana I. de Ávila ◽  
Esteban Domingo ◽  
Alejandro Brun
Keyword(s):  
Animal Models ◽  
Cell Cultures ◽  
Rift Valley ◽  
Rift Valley Fever ◽  
Rift Valley Fever Virus ◽  
Fever Virus ◽  
Nucleotide Sequence Analysis ◽  
African Countries ◽  
Valley Fever ◽  
Lethal Mutagenesis

ABSTRACTRift Valley fever virus (RVFV) is an emerging, mosquito-borne, zoonotic pathogen with recurrent outbreaks paying a considerable toll of human deaths in many African countries, for which no effective treatment is available. In cell culture studies and with laboratory animal models, the nucleoside analogue favipiravir (T-705) has demonstrated great potential for the treatment of several seasonal, chronic and emerging RNA virus infections of humans, suggesting applicability to control some viral outbreaks. Treatment with favipiravir was shown to reduce the infectivity of Rift Valley fever virus both in cell cultures and in experimental animal models, but the mechanism of this protective effect is not understood. In this work we show that favipiravir at concentrations well below the toxicity threshold estimated for cells is able to extinguish RVFV from infected cell cultures. Nucleotide sequence analysis has documented RVFV mutagenesis associated with virus extinction, with a significant increase in G to A and C to U transition frequencies, and a decrease of specific infectivity, hallmarks of lethal mutagenesis.

T-705 induces lethal mutagenesis in Ebola and Marburg populations in macaques

2019 ◽  
Vol 170 ◽  
pp. 104529 ◽  
Author(s):  
Nicole Espy ◽  
Elyse Nagle ◽  
Brad Pfeffer ◽  
Karla Garcia ◽  
Alex J. Chitty ◽  
...  
Keyword(s):  
Lethal Mutagenesis

scholarly journals Comparison of haplotype-based tests for detecting gene–environment interactions with rare variants

2019 ◽  
Vol 21 (3) ◽  
pp. 851-862 ◽  
Author(s):  
Charalampos Papachristou ◽  
Swati Biswas
Keyword(s):  
Lung Cancer ◽  
Rare Variants ◽  
Practical Interest ◽  
Serum Triglyceride ◽  
Error Rates ◽  
Type I ◽  
Rare Haplotype ◽  
Data Set ◽  
Cancer Data ◽  
Gene Environment

Abstract Dissecting the genetic mechanism underlying a complex disease hinges on discovering gene–environment interactions (GXE). However, detecting GXE is a challenging problem especially when the genetic variants under study are rare. Haplotype-based tests have several advantages over the so-called collapsing tests for detecting rare variants as highlighted in recent literature. Thus, it is of practical interest to compare haplotype-based tests for detecting GXE including the recent ones developed specifically for rare haplotypes. We compare the following methods: haplo.glm, hapassoc, HapReg, Bayesian hierarchical generalized linear model (BhGLM) and logistic Bayesian LASSO (LBL). We simulate data under different types of association scenarios and levels of gene–environment dependence. We find that when the type I error rates are controlled to be the same for all methods, LBL is the most powerful method for detecting GXE. We applied the methods to a lung cancer data set, in particular, in region 15q25.1 as it has been suggested in the literature that it interacts with smoking to affect the lung cancer susceptibility and that it is associated with smoking behavior. LBL and BhGLM were able to detect a rare haplotype–smoking interaction in this region. We also analyzed the sequence data from the Dallas Heart Study, a population-based multi-ethnic study. Specifically, we considered haplotype blocks in the gene ANGPTL4 for association with trait serum triglyceride and used ethnicity as a covariate. Only LBL found interactions of haplotypes with race (Hispanic). Thus, in general, LBL seems to be the best method for detecting GXE among the ones we studied here. Nonetheless, it requires the most computation time.

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