Prophylactic immunization prevents antiviral T cell subversion by a rat hepatitis C-like virus

Abstract

Abstract The hepatitis C virus (HCV) is a leading cause of severe progressive liver diseases by virtue of its ability to evade host immunity and establish lifelong persistence in majority of infected individuals. Despite significant advancements in antiviral therapy, a vaccine to prevent HCV persistence and associated disease is not yet available, in part because there is no small animal model to experimentally dissect mechanisms of immune protection and viral subversion. Here, we used a novel rat model of HCV-related hepacivirus infection to define antiviral T cell immunity during viral persistence and after prophylactic vaccination. Challenge of lab rats with a rodent hepacivirus led to universal persistence characterized by minimal viral diversification and an absence of functional CD8+ T cell responses. Direct visualization of virus-specific CD8+ T cells with a class I tetramer revealed a premature contraction of responses prior to acquisition of antiviral effector functions. By contrast, immunization of rats with a recombinant adenovirus expressing hepacivirus non-structural proteins induced functional CD4+ and CD8+ T cell immunity and significantly prevented hepacivirus persistence in majority of rats after challenge. Loss of vaccine-conferred immunity and subsequent persistence in a single rat was associated with selection of MHC class I escape variants. Transient depletion of CD8+ cells from vaccinated animals prolonged viral replication after challenge, while CD4+ cell depletion led to virus persistence. These data provide direct in vivo evidence that T cells are important for resolution of persistent hepacivirus infection and that subversion of the response can be successfully prevented by prophylactic immunization.