Model of influenza virus acidification

Area of Science:

• Virology
• Biophysics
• Computational Biology

Background:

• Influenza virus entry requires internal acidification mediated by the M2 proton channel.
• Dissolution of the M1 protein shell at pH 5.5-6.0 is essential for vRNA release.
• Existing models lack detailed kinetics of internal pH changes and external pH influence.

Purpose of the Study:

• To develop a mathematical model for M2-mediated virion acidification kinetics.
• To investigate the impact of endosomal maturation on internal viral pH.
• To predict the timing of internal pH changes relative to viral fusion.

Main Methods:

• Developed a mathematical model simulating M2 proton transport and virion acidification.
• Calculated the number of protons required for acidification.
• Applied the model to in vivo conditions with varying endosomal maturation rates.

Main Results:

• Approximately 32,000 protons are needed to acidify a typical virion.
• Internal acidification lagged behind endosomal acidification by ~1 minute.
• Fast endosomal maturation (<2 min) resulted in a significant lag, delaying M1 shell solvation.
• Internal pH reached solvation threshold just before external pH triggered hemagglutinin-mediated fusion.

Conclusions:

• The M2 channel's proton transport rate influences the timing of viral uncoating.
• The lag in internal acidification is critical for coordinating vRNA release and membrane fusion.
• Understanding these kinetics provides insights into influenza virus replication and potential therapeutic targets.