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Dengue Virus Evolution under a Host-Targeted Antiviral.
- Source :
-
Journal of virology [J Virol] 2015 May; Vol. 89 (10), pp. 5592-601. Date of Electronic Publication: 2015 Mar 11. - Publication Year :
- 2015
-
Abstract
- Unlabelled: The host-targeted antiviral drug UV-4B reduces viral replication and promotes survival in a mouse model of experimental dengue virus (DENV) infection. UV-4B is an iminosugar that inhibits the α-glucosidase family of enzymes and subsequently the folding of glycosylated proteins, both viral and host. Here, we utilized next-generation sequencing to investigate evolution of a flavivirus under selective pressure by a host-targeted antiviral in vivo. In viral populations recovered from UV-4B-treated mice, there was a significant increase in the number of single-nucleotide polymorphisms (SNPs) and the ratio of nonsynonymous to synonymous SNPs compared to findings in viral populations from vehicle-treated mice. The strongest evidence of positive selection was in the glycosylated membrane protein, thereby providing in vivo validation of the mechanism of action of an iminosugar. In addition, mutations in glycosylated proteins were present only in drug-treated mice after a single passage. However, the bulk of the other mutations were present in both populations, indicating nonspecific selective pressure. Together with the continued control of viremia by UV-4B, these findings are consistent with the previously predicted high genetic barrier to escape mutations in host-targeted antivirals.<br />Importance: Although hundreds of millions of people are infected with DENV every year, there is currently no approved vaccine or antiviral therapy. UV-4B has demonstrated antiviral activity against DENV and is expected to enter clinical trials soon. Therefore, it is important to understand the mechanisms of DENV resistance to UV-4B. Host-targeted antivirals are thought to have a higher genetic barrier to escape mutants than directly acting antivirals, yet there are very few published studies of viral evolution under host-targeted antivirals. No study to date has described flavivirus evolution in vivo under selective pressure by a host-based antiviral drug. We present the first in vivo study of the sequential progression of viral evolution under selective pressure by a host-targeted antiviral compound. This study bolsters support for the clinical development of UV-4B as an antiviral drug against DENV, and it provides a framework to compare how treatment with other host-targeted antiflaviviral drugs in humans and different animal models influence viral genetic diversity.<br /> (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Subjects :
- Animals
Dengue Virus physiology
Disease Models, Animal
Evolution, Molecular
Genetic Variation
Host-Pathogen Interactions drug effects
Humans
Imino Sugars pharmacology
Mice
Mice, 129 Strain
Mice, Knockout
Mutation
Polymorphism, Single Nucleotide
Selection, Genetic
Viral Proteins genetics
Virus Replication drug effects
Antiviral Agents pharmacology
Dengue drug therapy
Dengue virology
Dengue Virus drug effects
Dengue Virus genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1098-5514
- Volume :
- 89
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Journal of virology
- Publication Type :
- Academic Journal
- Accession number :
- 25762732
- Full Text :
- https://doi.org/10.1128/JVI.00028-15