Optimal control strategy for abnormal innate immune response.

Innate immune response plays an important role in control and clearance of pathogens following viral infection. However, in the majority of virus-infected individuals, the response is insufficient because viruses are known to use different evasion strategies to escape immune response. In this study, we use optimal control theory to investigate how to control the innate immune response. We present an optimal control model based on an ordinary-differential-equation system from a previous study, which investigated the dynamics and regulation of virus-triggered innate immune signaling pathways, and we prove the existence of a solution to the optimal control problem involving antiviral treatment or/and interferon therapy. We conduct numerical experiments to investigate the treatment effects of different control strategies through varying the cost function and control efficiency. The results show that a separate treatment, that is, only inhibiting viral replication (u1(t)) or enhancing interferon activity (u2(t)), has more advantages for controlling viral infection than a mixed treatment, that is, controlling both (u1(t)) and (u2(t)) simultaneously, including the smallest cost and operability. These findings would provide new insight for developing effective strategies for treatment of viral infectious diseases.

Mathematical modeling for intracellular transport and binding of HIV-1 Gag proteins.

This paper presents a modeling study for the intracellular trafficking and trimerization of the HIV-1 Gag proteins. A set of differential equations including initial and boundary conditions is used to characterize the transport, diffusion, association and dissociation of Gag monomers and trimers for the time period from the initial production of Gag protein monomers to the initial appearance of immature HIV-1 virions near the cell membrane (the time duration Ta). The existence and stability of the steady-state solution of the initial boundary value problems provide a quantitative characterization of the tendency and equilibrium of Gag protein movement. The numerical simulation results further demonstrate Gag trimerization near the cell membrane. Our calculations of Ta are in good agreement with published experimental data. Sensitivity analysis of Ta to the model parameters indicates that the timing of the initial appearance of HIV-1 virions on the cell membrane is affected by the diffusion and transport processes. These results provide important information and insight into the Gag protein transport and binding and HIV-1 virion formation.

Modeling and dynamical analysis of virus-triggered innate immune signaling pathways.

The investigation of the dynamics and regulation of virus-triggered innate immune signaling pathways at a system level will enable comprehensive analysis of the complex interactions that maintain the delicate balance between resistance to infection and viral disease. In this study, we developed a delayed mathematical model to describe the virus-induced interferon (IFN) signaling process by considering several key players in the innate immune response. Using dynamic analysis and numerical simulation, we evaluated the following predictions regarding the antiviral responses: (1) When the replication ratio of virus is less than 1, the infectious virus will be eliminated by the immune system's defenses regardless of how the time delays are changed. (2) The IFN positive feedback regulation enhances the stability of the innate immune response and causes the immune system to present the bistability phenomenon. (3) The appropriate duration of viral replication and IFN feedback processes stabilizes the innate immune response. The predictions from the model were confirmed by monitoring the virus titer and IFN expression in infected cells. The results suggest that the balance between viral replication and IFN-induced feedback regulation coordinates the dynamical behavior of virus-triggered signaling and antiviral responses. This work will help clarify the mechanisms of the virus-induced innate immune response at a system level and provide instruction for further biological experiments.