Fast-forwarding evolution-Accelerated adaptation in a proofreading-deficient hypermutator herpesvirus

Area of Science:

• Virology
• Evolutionary Biology
• Genetics

Background:

• DNA viruses require genetic diversity for evolution.
• High-fidelity DNA replication in viruses limits mutation rates.
• Studying DNA virus adaptation is challenging due to genetic stability.

Purpose of the Study:

• To develop a hypermutator Marek's disease virus (MDV) for accelerated evolutionary studies.
• To investigate the utility of hypermutator viruses in understanding adaptation and antiviral resistance.
• To explore the application of hypermutator viruses in vaccine design.

Main Methods:

• Generated a proofreading-impaired DNA polymerase mutant (Y547S) of MDV.
• Compared mutation frequencies between the Y547S mutant and wild-type (WT) MDV.
• Assessed the adaptation, antiviral evasion, and attenuation of the Y547S mutant.

Main Results:

• The Y547S mutant exhibited a 2-5 fold higher mutation frequency than WT MDV.
• Y547S demonstrated faster adaptation to non-permissive cells and enhanced evasion of antiviral inhibitors.
• Y547S showed more rapid attenuation during serial cell culture passage compared to WT.

Conclusions:

• Hypermutator viruses accelerate evolutionary processes, aiding the study of adaptation and antiviral resistance.
• Hypermutator MDV can be a valuable tool for identifying genetic changes related to host cell adaptation and antiviral evasion.
• Rapid attenuation of hypermutators in cell culture facilitates the identification of genetic determinants of virulence, useful for rational vaccine design.