T cells responses during resolving Hepacivirus A infection, a surrogate animal model for human Hepatitis C

Abstract

Abstract Hepacivirus A (HcV A) is a hepatotropic equine virus and the closest known relative of hepatitis C virus (HCV). HcV A is also highly similar to HCV in its replication kinetics and severity of associated acute hepatitis, but, unlike HCV, HcV A is typically cleared by the host before causing significant disease. As such, HcV A is considered a tenable model for defining the correlates of resolving hepaciviral infection and vaccine development. The pathogenesis of acute HcV A-hepatitis and the mechanism(s) that lead to viral clearance are unknown. In this study we aimed to characterize T cell responses in horses (n=2) following inoculation with plasma containing HcV A. Viremia and hepatic injury were monitored by RT-PCR and plasma liver enzyme activity [gamma glutamyl transferase (GGT) and sorbitol dehydrogenase (SDH)], respectively. HcV A-specific T-cell responses were evaluated every two weeks by interferon gamma Elispot following ex-vivo PBMC stimulation with peptides pools spanning the HcV A polyprotein. Liver biopsies were collected prior to infection, at the peak of liver enzyme activity, and following viral clearance to quantify CD4, CD8 and proinflammatory cytokine mRNA levels, and characterize CD3+ T cell infiltration by immunohistochemistry (IHC). No distinct HcV A specific peripheral T cell response was detected during infection, but when liver enzymes peaked, IHC revealed a mean 15 fold increase in CD3+ T cell infiltration. CD4, CD8 and proinflammatory cytokine mRNA levels were also significantly increased at the same time point. In conclusion, our findings suggest that acute HcV A-hepatitis is mediated by CD3+ T cells and that HcV A-specific T cell response are likely sequestered in the liver.