ADAPTATION OF A RAT DERIVED HCV-RELATED RODENT HEPACIVIRUS TO THE MOUSE HOST

Abstract

Hepatitis C is an infection caused by hepatitis C virus (HCV). This infection frequently evolves to a chronic condition, however, the mechanisms involved in the outcome of HCV infection are not completely understood. The current treatment for HCV, based on direct acting antiviral (DAA) agents is highly effective but expensive and it is also not clear if DAA-induced HCV cure, after decades long chronic infection, will prevent or reverse the development of serious virus-related liver disease. An HCV vaccine does not exist. The development of an efficient vaccine has been limited by the lack of a small model for HCV infection. The only immune-competent animal model of HCV infection, the chimpanzee, is no longer readily available for research. Many humanized and/or engineered mice have been developed to support the HCV life cycle. However, these models are based on significantly immune-compromised mouse strains. Hence they are not suitable to study antiviral immune responses, HCV pathogenesis or to test vaccine candidates. A new hope arose with the discovery of an HCV-related rodent hepacivirus in wild rats, named NrHV (Norway rat hepacivirus). Dr. Rice's lab recently showed that NrHV is capable to efficiently infect immune-competent wild type (WT) laboratory mice. However chronic infection could only be established if parts of the immune system were suppressed. In preliminary experiments Dr. Rice's team also showed that NrHV can be adapted to the murine host by passaging through mice with an impaired immune system. Therefore, the aim of this study is to explore NrHV adaptation to the murine host and to compare adapted-NrHV with its original infectious clone and then evaluate the gain of viral fitness in a fully immune-competent host. For that, innate-immune- knockout mice of the IFN/ISG pathways and mice with impaired adaptive immunity will be infected with NrHV and followed during adaptation period. Then WT mice will be infected with adapted and original NrHV. Viremia, ALT levels and chronicity will be evaluated. The adapted viruses capable to generate prolonged viremia, chronicity or elevated ALT levels in WT will be sequenced and the differences linked with adaptation in original infectious clone.