The role of cells refractory to productive infection in acute hepatitis B viral dynamics

Abstract

During acute hepatitis B virus (HBV) infection viral loads reach high levels ( approximately 10(10) HBV DNA per ml), and nearly every hepatocyte becomes infected. Nonetheless, approximately 85-95% of infected adults clear the infection. Although the immune response has been implicated in mediating clearance, the precise mechanisms remain to be elucidated. As infection clears, infected cells are replaced by uninfected ones. During much of this process the virus remains plentiful but nonetheless does not rekindle infection. Here, we analyze data from a set of individuals identified during acute HBV infection and develop mathematical models to test the role of immune responses in various stages of early HBV infection. Fitting the models to data we are able to separate the kinetics of the noncytolytic and the cytolytic immune responses, thus explaining the relative contribution of these two processes. We further show that we need to hypothesize that newly generated uninfected cells are refractory to productive infection. Without this assumption, viral resurgence is observed as uninfected cells are regenerated. Such protection, possibly mediated by cytokines, may also be important in resolving other acute viral infections.

Fig. 1.

Results of fitting the model to each patient's HBV DNA data and the relationship between effector cells and serum ALT during the acute phase of the infection. The best fit of the model (dashed lines) to HBV DNA patient data (∗) is indicated. The measured serum ALT (○), which was not used in data fitting, compares well with the predicted dynamics of the HBV-specific effector cell response (solid lines).

Fig. 2.

The predicted temporal relationship of the cytolytic and noncytolytic response to the level of infection and the HBV DNA viral load. Displayed for each patient are the measured HBV DNA (∗) and best-fit model predictions for: the HBV DNA viral load (dashed line), the number of refractory cells, R (solid line) and the productively infected cells, T* (dashed-dot line) (a); and noncytolytic immune response, ρT*(t)E(t)) (gold line), cytolytic immune response, μT∗(t)E(t)+μ₁R(t)E(t) (green line) (b). Note that the noncytolytic immune response occurs before the cytolytic response and peaks coincident with the viral load (red line).