Implications of decoupling the intracellular and extracellular levels in multi-level models of virus growth

Virus infections are characterized by two distinct levels of detail: the intracellular level describing how viruses hijack the host machinery to replicate, and the extracellular level describing how populations of virus and host cells interact. Deterministic, population balance models for viral infections permit incorporation of both the intracellular and extracellular levels of information. In this work, we identify assumptions that lead to exact, selective decoupling of the interaction between the intracellular and extracellular levels, effectively permitting solution of first the intracellular level, and subsequently the extracellular level. This decoupling leads to (1) intracellular and extracellular models of viral infections that have been previously reported and (2) a significant reduction in the computational expense required to solve the model. However, the decoupling restricts the behaviors that can be modeled. Simulation of a previously reported multi-level model demonstrates this decomposition when the intracellular level of description consists of numerous reaction events. Additionally, examples demonstrate that viruses can persist even when the intracellular level of description cannot sustain a steady-state production of virus (i.e., has only a trivial equilibrium). We expect the combination of this modeling framework with experimental data to result in a quantitative, systems-level understanding of viral infections and cellular antiviral strategies that will facilitate controlling both these infections and antiviral strategies.