Dengue Virus Evolution under a Host-Targeted Antiviral

Journal of Virology
Emily PlummerSujan Shresta

Abstract

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 barrie...Continue Reading

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Citations

Jan 16, 2016·Journal of Medicinal Chemistry·Mira A M BehnamChristian D Klein
Feb 14, 2016·Antiviral Research·Margot Carocci, Priscilla L Yang
Dec 8, 2015·European Journal of Medicinal Chemistry·Vicky C Roa-LinaresMiguel A González
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Feb 16, 2020·Medicinal Research Reviews·Xingyue Ji, Zhuorong Li
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Aug 20, 2019·Antiviral Research·Hussin A RothanShengyun Fang
Oct 30, 2020·International Journal of Molecular Sciences·Alexandra P M ClohertyFrançois Jean
Aug 10, 2020·Antiviral Research·Lisa Evans DeWaldKelly L Warfield

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