Mathematical Models of Early Hepatitis B Virus Dynamics in Humanized Mice

Abstract

Analyzing the impact of the adaptive immune response during acute hepatitis B virus (HBV) infection is essential for understanding disease progression and control. Here we developed mathematical models of HBV infection which either lack terms for adaptive immune responses, or assume adaptive immune responses in the form of cytolytic immune killing, non-cytolytic immune cure, or non-cytolytic-mediated block of viral production. We validated the model that does not include immune responses against temporal serum hepatitis B DNA (sHBV) and temporal serum hepatitis B surface-antigen (HBsAg) experimental data from mice engrafted with human hepatocytes (HEP). Moreover, we validated the immune models against sHBV and HBsAg experimental data from mice engrafted with HEP and human immune system (HEP/HIS). As expected, the model that does not include adaptive immune responses matches the observed high sHBV and HBsAg concentrations in all HEP mice. By contrast, while all immune response models predict reduction in sHBV and HBsAg concentrations in HEP/HIS mice, the Akaike Information Criterion cannot discriminate between non-cytolytic cure (resulting in a class of cells refractory to reinfection) and antiviral block functions (of up to $$99\%$$ 99 % viral production 1–3 weeks following peak viral load). We can, however, reject cytolytic killing, as it can only match the sHBV and HBsAg data when we predict unrealistic levels of hepatocyte loss.

Incorporating Intracellular Processes in Virus Dynamics Models

“…In the case of hepatitis B virus infection, mathematical models described by ordinary differential equations have been extensively used to investigate various aspects of the intracellular infection process [135][136][137]. In particular, they explored the role of HB-sAg production from integrated DNA in the process of HBV infection (checkpoint 5 in Figure 3) [138,139], they helped distinguish between the kinetics of the noncytolytic and cytolytic immune responses during acute HBV infection [140], and they investigated the impact of e-antigen (HBeAg) and HBsAg on inducing immunological tolerance during HBV infection [136,141]. Recently, a modified version of model Equation ( 6) (developed to study the effects of drugs on HCV infection) was adapted in order to describe the recycling of the intracellular covalently closed circular DNA (cccDNA) (checkpoint 8 in Figure 3).…”

Identifiability investigation of within-host models of acute virus infection

“…The study of host-virus interactions using dynamical models (within-host models) has improved our understanding of the mechanistic interactions that govern chronic [1][2][3][4] and acute [5][6][7][8][9][10][11][12] viral infections. Regardless of the virus considered, the most basic within-host model has a general structure that includes the interaction between the cells susceptible to the virus, the cells infected by the virus, and the virus at short (acute) and long (chronic) time-scales.…”