Does mutational robustness inhibit extinction by lethal mutagenesis in viral populations?

Area of Science:

• Virology
• Evolutionary Biology
• Computational Biology

Background:

• Lethal mutagenesis is an antiviral strategy that increases viral mutation rates to induce extinction.
• Viral genomes may evolve increased mutational robustness, potentially resisting this therapy.
• Understanding the interplay between robustness evolution and extinction is crucial for antiviral development.

Purpose of the Study:

• To investigate the extent to which mutational robustness can inhibit viral extinction induced by lethal mutagenesis.
• To assess the impact of robustness evolution on the mutation rate required for viral extinction.
• To determine the conditions under which robustness evolution becomes relevant on extinction timescales.

Main Methods:

• Utilized simple toy models and biophysically realistic models based on RNA secondary-structure folding.
• Employed an analytic multi-type branching process model.
• Performed stochastic calculations and simulations of self-replicating RNA sequences.

Main Results:

• Increased mutation rates can promote the evolution of greater mutational robustness.
• Robustness evolution is unlikely to significantly increase the mutation rate required for viral extinction.
• Robustness evolution is relevant only for small viral populations and mutation rates slightly above the extinction threshold.

Conclusions:

• The evolution of mutational robustness is generally unlikely to prevent viral extinction via lethal mutagenesis.
• Lethal mutagenesis remains a promising antiviral strategy despite potential viral adaptation.
• Further research may explore other viral resistance mechanisms or refine lethal mutagenesis protocols.