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research article

An experimental evaluation of drug-induced mutational meltdown as an antiviral treatment strategy

Bank, Claudia  
•
Renzette, Nicholas
•
Liu, Ping
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2016
Evolution

The rapid evolution of drug resistance remains a critical public health concern. The treatment of influenza A virus (IAV) has proven particularly challenging, due to the ability of the virus to develop resistance against current antivirals and vaccines. Here, we evaluate a novel antiviral drug therapy, favipiravir, for which the mechanism of action in IAV involves an interaction with the viral RNA-dependent RNA polymerase resulting in an effective increase in the viral mutation rate. We used an experimental evolution framework, combined with novel population genetic method development for inference from time-sampled data, to evaluate the effectiveness of favipiravir against IAV. Evaluating whole genome polymorphism data across 15 time points under multiple drug concentrations and in controls, we present the first evidence for the ability of IAV populations to effectively adapt to low concentrations of favipiravir. In contrast, under high concentrations, we observe population extinction, indicative of mutational meltdown. We discuss the observed dynamics with respect to the evolutionary forces at play and emphasize the utility of evolutionary theory to inform drug development.

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Type
research article
DOI
10.1111/evo.13041
Web of Science ID

WOS:000387072900004

Author(s)
Bank, Claudia  
Renzette, Nicholas
Liu, Ping
Matuszewski, Sebastian  
Shim, Hyunjin  
Foll, Matthieu
Bolon, Daniel N. A.
Zeldovich, Konstantin B.
Kowalik, Timothy F.
Finberg, Robert W.
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Date Issued

2016

Publisher

Wiley-Blackwell

Published in
Evolution
Volume

70

Issue

11

Start page

2470

End page

2484

Editorial or Peer reviewed

REVIEWED

Written at

EPFL

EPFL units
UPJENSEN  
Available on Infoscience
January 24, 2017
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/133713
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