A quantitative model for virus uncoating predicts influenza A infectivity

Area of Science:

• Virology
• Biophysics
• Molecular Biology

Background:

• Virus infection requires capsid disassembly for host cell entry.
• Mechanisms of influenza A virus (IAV) uncoating and host-virus interactions remain poorly understood.
• Understanding viral uncoating is crucial for developing antiviral strategies.

Purpose of the Study:

• To elucidate the mechanisms of influenza A virus (IAV) uncoating in host cells.
• To develop an experimentally supported multiscale kinetics model for viral uncoating.
• To identify host-virus interactions critical for viral entry and infectivity.

Main Methods:

• Multiscale kinetics modeling and biophysical modeling of viral capsid disassembly.
• Biochemical analysis to identify essential host factors and viral components.
• Biochemical-biophysical modeling to predict uncoating efficiency based on molecular interactions.

Main Results:

• A tug-of-war mechanism involving capsid M1 proteins, host histone deacetylase 6 (HDAC6), and molecular motors physically breaks the viral capsid.
• Unanchored ubiquitin chains are essential for efficient viral uncoating.
• A single amino acid variation in the M1 protein affecting HDAC6 binding explains differences in infectivity between viral strains.

Conclusions:

• The study presents a novel model elucidating IAV uncoating mechanisms.
• Host-viral interactions, particularly M1-HDAC6 binding, are critical determinants of viral infectivity.
• Identified mechanisms and models offer potential for developing broad-range antiviral treatments.