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Abstract
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.
Development of a HCV vaccine is hampered by a lack of appropriate small animal models. Here, Hartlage et al. describe a rat model of hepacivirus persistence and show that persistence can be prevented by vaccination with viral non-structural proteins.
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1 The Research Institute at Nationwide Children’s Hospital, Center for Vaccines and Immunity, Columbus, USA (GRID:grid.240344.5) (ISNI:0000 0004 0392 3476); The Ohio State University, Medical Scientist Training Program, College of Medicine and Public Health, Columbus, USA (GRID:grid.261331.4) (ISNI:0000 0001 2285 7943)
2 The Research Institute at Nationwide Children’s Hospital, Center for Vaccines and Immunity, Columbus, USA (GRID:grid.240344.5) (ISNI:0000 0004 0392 3476)
3 The Research Institute at Nationwide Children’s Hospital, Center for Vaccines and Immunity, Columbus, USA (GRID:grid.240344.5) (ISNI:0000 0004 0392 3476); The Ohio State University, Department of Pediatrics, College of Medicine and Public Health, Columbus, USA (GRID:grid.261331.4) (ISNI:0000 0001 2285 7943)