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 (Ϸ10 10 HBV DNA per ml), and nearly every hepatocyte becomes infected. Nonetheless, Ϸ85-95% 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.immune response ͉ mathematical modeling ͉ viral kinetics H epatitis B virus (HBV) is a small (Ϸ3.2 kb) partially dsDNA virus that infects hepatocytes (1). There are Ͼ350 million chronic HBV carriers worldwide, and infection with HBV is the cause of significant morbidity and mortality in countries of high prevalence (2). During acute infection, HBV viral loads can reach high levels, up to 10 10 HBV DNA copies per ml of plasma, which last for several weeks, coincident with HBV infection of a large percentage of hepatocytes (3-6). Subsequently, viral loads decrease, and in 85-95% of acutely infected adults the infection is cleared (7). Patients that clear the virus tend to have stronger and more diversified CD4 ϩ and CD8 ϩ T cell responses (8, 9). In addition, clearance of the virus in acutely infected patients is usually accompanied by an alanine aminotransferase (ALT) flare. Elevated levels of ALT are indicative of liver damage and an active cell-mediated immune response. Although the immune response plays a crucial role in decreasing the viral load, the precise mechanisms are not fully understood (10).Studying the immune response to HBV during acute infection of humans is difficult, and the field has progressed by the study of experimental infection in chimpanzees, woodchucks, and ducks and transgenic mice that express HBV genes. These studies demonstrated the importance of the immune response, because acute infection in chimpanzees depleted of CD8 ϩ T cells results in delayed HBV clearance and recovery (11). However, chimpanzee studies have also shown that the initial reduction in HBV viral load occurs much earlier than any detectable cytolytic immune response, liver T cell infiltration, or liver damage (3), suggesting that some form of noncytolytic response is involved. The importance of a noncytolytic response has been conf...

Mathematical models of the interrelated dynamics of hepatitis D and B

“…This general framework stems from simple, linear models [12] which have been refined and improved upon over time, as there are many rich HBV models in the literature [13][14][15][16][17]. For an initial HDV model, we begin with the ODE model proposed in Hews et al [18], which produces rich and biologically meaningful dynamics by replacing the traditional mass action infection terms with nonlinear but more realistic rate functions [13] …”

“…From the context of chronic HBV-HDV infection and lamivudine, it is reasonable to assume that infected cells should proliferate at rates sufficient to sustain infection. Empirically driven models of HBV have also included infected cell proliferation [15,24].…”

A mathematical model of the intracellular replication and within host evolution of hepatitis type B virus: Understanding the long time course of chronic hepatitis

“…Though the intracellular dynamics addressed in this study cannot be directly compared with the virion in the basic model of HBV infection shown in the previous studies (Payne et al, 1994;Nowak et al, 1996;Payne et al, 1996;Tsiang et al, 1999;Lau et al, 2000;Ciupe et al, 2007a;Ciupe et al, 2007b), the amount of virion calculated from our model is related to the production rate of virion that is assumed as constant in these studies. Some parameters in our model such as association rate between the core particle and surface protein are difficult to directly measure.…”

“…It is reported that the clinical course of hepatitis is explained as the dynamics of infectious hepatocytes by using mathematical models (Payne et al, 1994;Nowak et al, 1996;Payne et al, 1996;Tsiang et al, 1999;Lau et al, 2000;Columbatto et al, 2006;Ciupe et al, 2007a;Ciupe et al, 2007b). In these papers, it is assumed that HBV virion is constantly produced with a certain rate from infected hepatocyte.…”

Optimal Control of Drug Therapy in a Hepatitis B Model

“…Mathematical models have been used to address transition from acute to chronic HBV infections [13][14][15][16] and to study the effects of drug therapy [17][18][19]. Optimal control theory was developed by Pontryagin et al for obtaining necessary conditions to characterize optimal controls for systems of ordinary differential equations (ODEs) [20].…”