A Spatial Whole-Cell Model for Hepatitis B Viral Infection and Drug Interactions

Abstract

Despite a vaccine, hepatitis B remains a world-wide source of infections and deaths, and tackling the infection requires a multimodal approach against the virus. We develop a whole-cell model combining spatial and kinetic models for the infection cycle of a hepatocyte by hepatitis B virus (HBV). We simulate a near complete viral infection cycle with this whole cell model stochastically for 10 minutes of biological time, as a starting point to map out virus-host interaction. We find that with an established infection, decreasing the copy number of envelope proteins can shift the dominant infection pathways to amplification, resulting in higher cccDNA copy number, which may be a mode of action for siRNA drugs. Capsid mutants when destabilized such that they disassemble at nuclear pore complexes lead to increase in cccDNA copy number, but a cytoplasmic disassembly does not increase cccDNA copy number. Finally, our simulations can predict the best drug dosage and timing of administration. Our adaptable computational platform can be utilized to study other viruses and host-virus interactions.