Abstract:
:Predicting and constraining RNA virus evolution require understanding the molecular factors that define the mutational landscape accessible to these pathogens. RNA viruses typically have high mutation rates, resulting in frequent production of protein variants with compromised biophysical properties. Their evolution is necessarily constrained by the consequent challenge to protein folding and function. We hypothesized that host proteostasis mechanisms may be significant determinants of the fitness of viral protein variants, serving as a critical force shaping viral evolution. Here, we test that hypothesis by propagating influenza in host cells displaying chemically-controlled, divergent proteostasis environments. We find that both the nature of selection on the influenza genome and the accessibility of specific mutational trajectories are significantly impacted by host proteostasis. These findings provide new insights into features of host-pathogen interactions that shape viral evolution, and into the potential design of host proteostasis-targeted antiviral therapeutics that are refractory to resistance.
journal_name
Elifejournal_title
eLifeauthors
Phillips AM,Gonzalez LO,Nekongo EE,Ponomarenko AI,McHugh SM,Butty VL,Levine SS,Lin YS,Mirny LA,Shoulders MDdoi
10.7554/eLife.28652subject
Has Abstractpub_date
2017-09-26 00:00:00issn
2050-084Xjournal_volume
6pub_type
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