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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM057756-16
Application #
8534141
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Eckstrand, Irene A
Project Start
1998-01-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
16
Fiscal Year
2013
Total Cost
$199,262
Indirect Cost
$70,290
Name
University of Texas Austin
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78712
Paff, Matthew L; Stolte, Steven P; Bull, James J (2014) Lethal mutagenesis failure may augment viral adaptation. Mol Biol Evol 31:96-105
Bull, James J; Vegge, Christina Skovgaard; Schmerer, Matthew et al. (2014) Phenotypic resistance and the dynamics of bacterial escape from phage control. PLoS One 9:e94690
Bull, James J; Joyce, Paul; Gladstone, Eric et al. (2013) Empirical complexities in the genetic foundations of lethal mutagenesis. Genetics 195:541-52
Cecchini, Nicole; Schmerer, Matthew; Molineux, Ian J et al. (2013) Evolutionarily stable attenuation by genome rearrangement in a virus. G3 (Bethesda) 3:1389-97
Chantranupong, Lynne; Heineman, Richard H (2012) A common, non-optimal phenotypic endpoint in experimental adaptations of bacteriophage lysis time. BMC Evol Biol 12:37
Nguyen, Andre H; Molineux, Ian J; Springman, Rachael et al. (2012) Multiple genetic pathways to similar fitness limits during viral adaptation to a new host. Evolution 66:363-74
Bull, J J; Otto, G; Molineux, I J (2012) In vivo growth rates are poorly correlated with phage therapy success in a mouse infection model. Antimicrob Agents Chemother 56:949-54
Bull, J J; Molineux, I J; Wilke, C O (2012) Slow fitness recovery in a codon-modified viral genome. Mol Biol Evol 29:2997-3004
Bull, James J; Heineman, Richard H; Wilke, Claus O (2011) The phenotype-fitness map in experimental evolution of phages. PLoS One 6:e27796
Springman, R; Keller, T; Molineux, I J et al. (2010) Evolution at a high imposed mutation rate: adaptation obscures the load in phage T7. Genetics 184:221-32

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