scholarly journals Molecular determinants of Yellow Fever Virus pathogenicity in Syrian Golden Hamsters: one mutation away from virulence

2018 ◽  
Author(s):  
Raphaëlle Klitting ◽  
Laura Roth ◽  
Félix A. Rey ◽  
Xavier de Lamballerie
Keyword(s):  
Yellow Fever ◽  
Reverse Genetics ◽  
Yellow Fever Virus ◽  
Virulent Strain ◽  
Fever Virus ◽  
Viral Loads ◽  
Synonymous Mutations ◽  
E Protein ◽  
Α Helix

ABSTRACTYellow fever virus (Flavivirusgenus) is an arthropod-borne pathogen which can infect humans, causing a severe viscerotropic disease with a high mortality rate. Adapted viral strains allow the reproduction of yellow fever disease in hamsters with features similar to the human disease. Here, we used the Infectious Subgenomic Amplicons reverse genetics method to produce an equivalent to the hamster-virulent strain, Yellow FeverAp7, by introducing a set of 4 synonymous and 6 non-synonymous mutations into a single subgenomic amplicon, derived from the sequence of theAsibistrain. The resulting strain, Yellow FeverAp7M, induced a disease similar to that described forAp7in terms of symptoms, weight evolution, viral loads in the liver and lethality. Using the same methodology, we produced mutant strains derived from eitherAp7MorAsibiviruses and investigated the role of each ofAp7Mnon-synonymous mutations in itsin vivophenotype. This allowed identifying key components of the virulence mechanism in hamsters. InAp7Mvirus, the reversion of either E/Q27H or E/D155A mutations, led to an important reduction of both virulence andin vivoreplicative fitness. In addition, the introduction of the single D155AAp7Mmutation within the E protein of theAsibivirus was sufficient to drastically modify its phenotype in hamsters towards both a greater replication efficiency and virulence. Finally, inspection of theAsibistrain E protein structure combined toin vivotesting revealed the importance of an exposed α-helix in domain I, containing residues 154 and 155, forAp7Mvirulence in hamsters.

scholarly journals E Protein Domain III Determinants of Yellow Fever Virus 17D Vaccine Strain Enhance Binding to Glycosaminoglycans, Impede Virus Spread, and Attenuate Virulence

2008 ◽  
Vol 82 (12) ◽  
pp. 6024-6033 ◽  
Author(s):  
Eva Lee ◽  
Mario Lobigs
Keyword(s):  
Yellow Fever ◽  
Yellow Fever Virus ◽  
Fever Virus ◽  
Protein Domain ◽  
Type I ◽  
Wild Type ◽  
E Protein ◽  
Virulence Attenuation ◽  
Domain Iii

ABSTRACT The yellow fever virus (YFV) 17D strain is one of the most effective live vaccines for human use, but the in vivo mechanisms for virulence attenuation of the vaccine and the corresponding molecular determinants remain elusive. The vaccine differs phenotypically from wild-type YFV by the loss of viscerotropism, despite replicative fitness in cell culture, and genetically by 20 amino acid changes predominantly located in the envelope (E) protein. We show that three residues in E protein domain III inhibit spread of 17D in extraneural tissues and attenuate virulence in type I/II interferon-deficient mice. One of these residues (Arg380) is a dominant glycosaminoglycan-binding determinant, which mainly accounts for more rapid in vivo clearance of 17D from the bloodstream in comparison to 17D-derived variants with wild-type-like E protein. While other mutations will account for loss of neurotropism and phenotypic stability, the described impact of E protein domain III changes on virus dissemination and virulence is the first rational explanation for the safety of the 17D vaccine in humans.

scholarly journals In Silico Approach To Design a B-cell Epitope Based Vaccine Target Against Yellow Fever Virus

2019 ◽  
Vol 35 (1) ◽  
pp. 27-35
Author(s):  
Shamira Tabrejee ◽  
M Mahboob Hossain
Keyword(s):  
Yellow Fever ◽  
Yellow Fever Virus ◽  
Peptide Vaccine ◽  
Cell Epitope ◽  
Epitope Prediction ◽  
Fever Virus ◽  
Young Infants ◽  
E Protein

Yellow fever virus is a prototype member of the Flaviviridae family causing high fever and jaundice. Though YF 17D vaccine is administered to yellow fever patients, however it can produce adverse effects in immunocompromised, older people and young infants. The aim of this study is to design an epitope-based peptide vaccine by targeting envelope (E) protein of Yellow Fever Virus. Thirty sequences of E protein of Yellow Fever Virus strains were retrieved from NCBI database. E protein was found to be mostly conserved among all the sequences with little variability and also was identified as a probable antigen. Different epitope prediction tools predicted 4 common epitopes, 3 of which were found to be antigenic. A peptide VKNPTDTGin E protein was predicted to have surface accessibility which overlaps with the VKNPTDTGHGT epitope.So, the whole VKNPTDTGHGT epitope was taken for further analysis. The VKNPTDTGHGT epitope showed 96.67% conservancy and also possesses flexibility, hydrophilicity and non-toxicity. Therefore, VKNPTDTGHGT can be regarded as a potential vaccine candidate against Yellow fever virus with further in vitro and in vivo validation. Bangladesh J Microbiol, Volume 35 Number 1 June 2018, pp 27-35

scholarly journals Exploratory re-encoding of Yellow Fever Virus genome: new insights for the design of live-attenuated viruses

2018 ◽  
Author(s):  
R. Klitting ◽  
T. Riziki ◽  
G. Moureau ◽  
G. Piorkowski ◽  
E. A. Gould ◽  
...  
Keyword(s):  
Yellow Fever ◽  
Yellow Fever Virus ◽  
Fever Virus ◽  
Coding Region ◽  
Live Attenuated Vaccine ◽  
Replicative Fitness ◽  
Synonymous Mutations ◽  
Attenuated Viruses

AbstractVirus attenuation by genome re-encoding is a pioneering approach for generating effective live-attenuated vaccine candidates. Its core principle is to introduce a large number of synonymous substitutions into the viral genome to produce stable attenuation of the targeted virus. Introduction of large numbers of mutations has also been shown to maintain stability of the attenuated phenotype by lowering the risk of reversion and recombination of re-encoded genomes. Identifying mutations with low fitness cost is pivotal as this increases the number that can be introduced and generates more stable and attenuated viruses. Here, we sought to identify mutations with low deleterious impact on thein vivoreplication and virulence of yellow fever virus (YFV). Following comparative bioinformatic analyses of flaviviral genomes, we categorized synonymous transition mutations according to their impact on CpG/UpA composition and secondary RNA structures. We then designed 17 re-encoded viruses with 100-400 synonymous mutations in the NS2A-to-NS4B coding region of YFVAsibiandAp7M(hamster-adapted) genomes. Each virus contained a panel of synonymous mutations designed according to the above categorisation criteria. The replication and fitness characteristics of parent and re-encoded viruses were comparedin vitrousing cell culture competition experiments.In vivolaboratory hamster models were also used to compare relative virulence and immunogenicity characteristics. Most of the re-encoded strains showed no decrease in replicative fitnessin vitro. However, they showed reduced virulence and, in some instances, decreased replicative fitnessin vivo. Importantly, the most attenuated of the re-encoded strains induced robust, protective immunity in hamsters following challenge withAp7M, a virulent virus. Overall, the introduction of transitions with no or a marginal increase in the number of CpG/UpA dinucleotides had the mildest impact on YFV replication and virulencein vivo. Thus, this strategy can be incorporated in procedures for the finely tuned creation of substantially re-encoded viral genomes.

scholarly journals Yellow fever virus is susceptible to sofosbuvir both in vitro and in vivo

2019 ◽  
Vol 13 (1) ◽  
pp. e0007072 ◽  
Author(s):  
Caroline S. de Freitas ◽  
Luiza M. Higa ◽  
Carolina Q. Sacramento ◽  
André C. Ferreira ◽  
Patrícia A. Reis ◽  
...  
Keyword(s):  
Yellow Fever ◽  
Yellow Fever Virus ◽  
Fever Virus

Location of a neutralization determinant in the E protein of yellow fever virus (17D vaccine strain)

Virology ◽  
1987 ◽  
Vol 161 (2) ◽  
pp. 474-478 ◽  
Author(s):  
M. Lobigs ◽  
L. Dalgarno ◽  
J.J. Schlesinger ◽  
R.C. Weir
Keyword(s):  
Yellow Fever ◽  
Vaccine Strain ◽  
Yellow Fever Virus ◽  
Fever Virus ◽  
E Protein

scholarly journals Production of Pseudoinfectious Yellow Fever Virus with a Two-Component Genome

2007 ◽  
Vol 81 (21) ◽  
pp. 11737-11748 ◽  
Author(s):  
Alexandr V. Shustov ◽  
Peter W. Mason ◽  
Ilya Frolov
Keyword(s):  
Yellow Fever ◽  
Yellow Fever Virus ◽  
Fever Virus ◽  
Structural Proteins ◽  
Multiplicity Of Infection ◽  
Nonstructural Proteins ◽  
Replication Complex ◽  
Packaging Process ◽  
E Protein ◽  
Two Component

ABSTRACT Application of genetically modified, deficient-in-replication flaviviruses that are incapable of developing productive, spreading infection is a promising means of designing safe and effective vaccines. Here we describe a two-component genome yellow fever virus (YFV) replication system in which each of the genomes encodes complete sets of nonstructural proteins that form the replication complex but expresses either only capsid or prM/E instead of the entire structural polyprotein. Upon delivery to the same cell, these genomes produce together all of the viral structural proteins, and cells release a combination of virions with both types of genomes packaged into separate particles. In tissue culture, this modified YFV can be further passaged at an escalating scale by using a high multiplicity of infection (MOI). However, at a low MOI, only one of the genomes is delivered into the cells, and infection cannot spread. The replicating prM/E-encoding genome produces extracellular E protein in the form of secreted subviral particles that are known to be an effective immunogen. The presented strategy of developing viruses defective in replication might be applied to other flaviviruses, and these two-component genome viruses can be useful for diagnostic or vaccine applications, including the delivery and expression of heterologous genes. In addition, the achieved separation of the capsid-coding sequence and the cyclization signal in the YFV genome provides a new means for studying the mechanism of the flavivirus packaging process.

scholarly journals Innovative in cellulo method as an alternative to in vivo neurovirulence test for the characterization and quality control of human live Yellow Fever virus vaccines: A pilot study

Biologicals ◽  
2018 ◽  
Vol 53 ◽  
pp. 19-29 ◽  
Author(s):  
Anaelle da Costa ◽  
Christophe Prehaud ◽  
Cecile Khou ◽  
Nathalie Pardigon ◽  
Aure Saulnier ◽  
...  
Keyword(s):  
Quality Control ◽  
Pilot Study ◽  
Yellow Fever ◽  
Yellow Fever Virus ◽  
Fever Virus
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