This work will investigate the evolution of viruses subjected to a sustained, high mutation rate. Evolution at a high mutation rate is expected to reduce population fitness by the progressive accumulation of deleterious mutations;high rates can even cause population extinction, a process known as lethal mutagenesis. This principle underlies the common use of mutagenic, drugs to treat viral infections clinically. Here, viruses (bacteriophages) will be grown in vitro at different levels of mutagenesis and the evolutionary consequences of that mutagenesis will be studied.
In Aim 1, viral fitness evolution will be compared with a model predicting the amount of fitness decline based on the estimated deleterious mutation rate and viral life history parameters. Robustness of the model will be evaluated by (i) varying the mutation rate between high levels expected to cause extinction and lower levels, (ii) evolving viruses with and without recombination, and (iii) studying viruses with RNA genomes and others with DNA genomes. A preliminary study already observed the evolution of much higher viral fitness than predicted (due to viral adaptation), and special attention will be given to the factors contributing to viral adaptation during mutagenic treatment.
In Aim 2, populations of viruses surviving mutagenic treatment will be assayed for elevated frequencies of beneficial phenotypes (e.g., ability to grow on inhibitors), to address whether failed lethal mutagenesis might accelerate evolution in counter-productive ways.
In Aim 3, viral populations that survived mutagenic treatment and isolates from those populations will be evolved in the absence of mutagenesis. The question here is how long the mutational load from mutagenic treatment will depress fitness below wild-type levels after treatment is stopped. Collectively, these studies should provide a foundation for interpreting and designing efforts at lethal mutagenesis in vivo.

Public Health Relevance

Some antiviral drugs elevate the mutation rate of the virus. It has been proposed that the elevated mutation rate contributes to curing the infection (extinction through 'lethal mutagenesis'), but the mutagenic drugs are often not successful. The work here will investigate the foundations of lethal mutagenesis and whether the elevated mutation rate might instead lead to enhanced viral evolution.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Genetic Variation and Evolution Study Section (GVE)
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Eckstrand, Irene A
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University of Texas Austin
Schools of Arts and Sciences
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Paff, Matthew L; Nuismer, Scott L; Ellington, Andrew et al. (2016) Virus wars: using one virus to block the spread of another. PeerJ 4:e2166
Bull, James J (2016) Lethal gene drive selects inbreeding. Evol Med Public Health 2017:1-16
Paff, Matthew L; Nuismer, Scott L; Ellington, Andrew D et al. (2016) Design and engineering of a transmissible antiviral defense. J Biol Eng 10:12
Bull, James J; Crandall, Cameron; Rodriguez, Anna et al. (2015) Models for the directed evolution of bacterial allelopathy: bacteriophage lysins. PeerJ 3:e879
Bull, J J (2015) Evolutionary decay and the prospects for long-term disease intervention using engineered insect vectors. Evol Med Public Health 2015:152-66
Bull, J J (2015) Evolutionary reversion of live viral vaccines: Can genetic engineering subdue it? Virus Evol 1:
Paff, Matthew L; Stolte, Steven P; Bull, James J (2014) Lethal mutagenesis failure may augment viral adaptation. Mol Biol Evol 31:96-105
Schmerer, Matthew; Molineux, Ian J; Bull, James J (2014) Synergy as a rationale for phage therapy using phage cocktails. PeerJ 2:e590
Bull, James J; Lauring, Adam S (2014) Theory and empiricism in virulence evolution. PLoS Pathog 10:e1004387
Schmerer, Matthew; Molineux, Ian J; Ally, Dilara et al. (2014) Challenges in predicting the evolutionary maintenance of a phage transgene. J Biol Eng 8:21

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