Please use this identifier to cite or link to this item: https://biore.bio.bg.ac.rs/handle/123456789/1153
Title: Chikungunya virus overcomes polyamine depletion by mutation of nsP1 and the opal stop codon to confer enhanced replication and fitness
Authors: Mounce, Bryan
Cesaro, Teresa
Vlajnić, Lea 
Vidiņa, Anna
Vallet, Thomas
Weger-Lucarelli, James
Passoni, Gabriella
Stapleford, Kenneth
Levraud, Jean Pierre
Vignuzzi, Marco
Keywords: Antiviral;Antiviral resistance;Chikungunya virus;Polyamines;Viral replication
Issue Date: 1-Aug-2017
Publisher: American Society for Microbiology
Journal: Journal of Virology
Abstract: 
Polyamines, which are small positively charge molecules present in all cells, play important roles in the replication of DNA and RNA viruses. Chikungunya virus (CHIKV) relies on polyamines for translation of the viral genome upon viral entry, and pharmacological depletion of polyamines limits viral replication. However, the potential development of antiviral resistance necessitates a better understanding of how polyamines function and can be targeted via compounds that alter polyamine levels. We have isolated CHIKV that is resistant to polyamine depletion and contains two mutations in the nonstructural protein 1 (nsP1)-coding region in combination with a mutation to the opal stop codon preceding nsP4. These mutations, in addition to promoting viral replication in polyamine-depleted cells, confer enhanced viral replication in vitro and in vivo. The nsP1 mutations enhance membrane binding and methyltransferase activities, while the stop codon mutation allows increased downstream translation. These mutations, when combined, enhance viral fitness, but individual mutants are attenuated in mosquitoes. Together, our results suggest that CHIKV can evolve resistance to polyamine depletion and that pharmaceuticals targeting the polyamine biosynthetic pathway may be best used in combination with other established antivirals to mitigate the development of resistance.
URI: https://biore.bio.bg.ac.rs/handle/123456789/1153
ISSN: 0022-538X
DOI: 10.1128/JVI.00344-17
Appears in Collections:Journal Article

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