Tradeoffs for a viral mutant with enhanced replication speed.

Area of Science:

• Virology
• Molecular Biology
• Genetics

Background:

• RNA viruses exhibit genetic heterogeneity due to high mutation rates, often impacting replication speed and fitness.
• The potential for viral mutations to increase replication speed in well-adapted viruses remains largely unexplored.

Purpose of the Study:

• To investigate if mutations can enhance viral replication speed in coxsackievirus B3 already adapted to cell culture.
• To identify specific mutations responsible for increased replication speed and characterize their effects on viral fitness.

Main Methods:

• Sequential passaging of coxsackievirus B3 in cultured cells to select for rapid replication.
• Genetic sequencing to identify mutations associated with the fast-replication phenotype.
• In vitro characterization of viral mutants, including genome release kinetics, capsid stability, and replication efficiency in cell culture and mice.

Main Results:

• A single mutation, VP1-F106L, in the viral capsid protein was sufficient to confer a fast-replication phenotype.
• The VP1-F106L mutation accelerated genome release during viral entry, indicating a novel infection barrier.
• Despite increased replication speed, the mutation reduced in vitro capsid stability and decreased viral replication and pathogenesis in mouse models.

Conclusions:

• A tradeoff exists between viral replication speed and overall fitness, as demonstrated by the VP1-F106L mutation.
• The selection strategy of isolating earliest viral progeny can uncover previously unrecognized viral replication cycle inefficiencies.
• This approach holds potential for studying diverse viral systems and identifying novel antiviral targets.