Vaccination to prevent T cell subversion can protect against persistent hepacivirus infection

Efforts to develop an effective vaccine against the hepatitis C virus (HCV; human hepacivirus) have been stymied by a lack of small animal models. Here, we describe an experimental rat model of chronic HCV-related hepacivirus infection and its response to T cell immunization. Immune-competent rats challenged with a rodent hepacivirus (RHV) develop chronic viremia characterized by expansion of non-functional CD8⁺ T cells. Single-dose vaccination with a recombinant adenovirus vector expressing hepacivirus non-structural proteins induces effective immunity in majority of rats. Resolution of infection coincides with a vigorous recall of intrahepatic cellular responses. Host selection of viral CD8 escape variants can subvert vaccine-conferred immunity. Transient depletion of CD8⁺ cells from vaccinated rats prolongs infection, while CD4⁺ cell depletion results in chronic viremia. These results provide direct evidence that co-operation between CD4⁺ and CD8⁺ T cells is important for hepacivirus immunity, and that subversion of responses can be prevented by prophylactic vaccination.