Modeling suggests that virion production cycles within individual cells is key to understanding acute hepatitis B virus infection kinetics

Author summaryA surprisingly complex hepatitis B virus (HBV) infection kinetics was observed in chimeric urokinase type plasminogen activator transgenic, severe combined immunodeficient (uPA-SCID) mice with humanized livers. Here we developed an agent-based model (ABM) to reproduce the observed multiphasic HBV dynamics. To model the fundamental cyclic dynamics of viral infections (i.e., the underlying viral lifecycle), capture the inherent asynchronous nature of viral infections, and mimic the amplification of these successive virion release cycles from individual cells, our newly developed ABM approach enables conceptualization of discrete virus production as cycles allowing for accurate recapitulation of the complex kinetic pattern observed in vivo and providing new theoretical frontiers to understanding viral dynamics. Hepatitis B virus (HBV) infection kinetics in immunodeficient mice reconstituted with humanized livers from inoculation to steady state is highly dynamic despite the absence of an adaptive immune response. To recapitulate the multiphasic viral kinetic patterns, we developed an agent-based model that includes intracellular virion production cycles reflecting the cyclic nature of each individual virus lifecycle. The model fits the data well predicting an increase in production cycles initially starting with a long production cycle of 1 virion per 20 hours that gradually reaches 1 virion per hour after approximately 3-4 days before virion production increases dramatically to reach to a steady state rate of 4 virions per hour per cell. Together, modeling suggests that it is the cyclic nature of the virus lifecycle combined with an initial slow but increasing rate of HBV production from each cell that plays a role in generating the observed multiphasic HBV kinetic patterns in humanized mice.