Mathematical modeling was performed to test the extent to which cytopathic and noncytopathic T cell effector functions contribute to resolution of hepatitis B virus (HBV) infection in three acutely infected chimpanzees. Simulations based exclusively on cytopathic functions show a poor fit to the data and would require the destruction and regeneration of Ϸ11 livers for clearance to occur. In contrast, a simulation based on a combination of cytopathic and noncytopathic functions provided a significantly better fit to the data (P < 0.001) and required as much as 5-fold less destruction to clear the virus from the liver. The best fit simulation supports the notion that during the early phase of HBV clearance, noncytopathic T cell effector mechanisms inhibit viral replication and greatly shorten the half-life of the long lived covalently closed circular viral DNA transcriptional template, thereby limiting the extent to which cytopathic T cell effector functions and tissue destruction are required to terminate acute HBV infection.mathematical modeling ͉ pathogenesis ͉ covalently closed circular DNA T he hepatitis B virus (HBV) is a noncytopathic, hepatotropic, DNA virus (hepadnavirus) that causes acute and chronic hepatitis and hepatocellular carcinoma (1). Although it is generally agreed that viral clearance and disease pathogenesis during HBV infection are mediated by the immune response (2-6), the extent to which cytopathic and noncytopathic CD8ϩ T cell antiviral functions contribute to these events is a matter of some debate (7-11). On the one hand, it has been amply demonstrated that termination of acute hepadnavirus infections in the woodchuck (7, 12) and chimpanzee (9-11) systems is associated with the destruction of infected cells and hepatocellular regeneration (7)(8)(9)(10)(12)(13)(14)(15). On the other hand, it is equally clear from chimpanzee (9-11) and transgenic mouse (16,17) experiments, that HBV replication is strongly inhibited by the antiviral effects of inflammatory cytokines produced by HBVspecific CD8 ϩ T cells when they recognize antigen in the infected or transgenic liver. Furthermore, it has been shown that viral clearance in acutely infected chimpanzees is heralded by a sharp drop in the HBV DNA content of the liver, which depends on the influx of IFN-␥-producing CD8 ϩ T cells into the liver (10), but which precedes and is out of proportion to the amount of liver disease (10). Moreover, in the transgenic mouse model, adoptively transferred HBV-specific CD8 ϩ T cells have been shown to inhibit HBV replication by an IFN-␥-dependent mechanism (16), even when they cannot cause hepatitis because their cytolytic effector functions have been abrogated genetically (16). On the other hand, HBV replication proceeds unabated when IFN-␥-deficient CD8 ϩ T cells are injected into HBV transgenic mice despite the induction of liver disease.Although noncytolytic inhibition of HBV replication by CD8 ϩ T cell-derived antiviral cytokines is sufficient to prevent the production of new virus particles and, therefor...