Hepatitis C virus is a leading cause of liver disease worldwide, yet little is understood about Hepatitis C virus (HCV) in vivo because HCV only infects humans and chimpanzees, and thus capacity for experimentation is limited. HCV is complex and establishes lifelong persistence in 60-80% of infected individuals, increasing the risk of liver cirrhosis and hepatocellular carcinoma; therefore, the need for an applicable, immunocompetent animal model is great. A team of researchers, including CIDD’s Kurt Vandegrift and led by Sheetal Trivedi (The Research Institute at Nationwide Children’s Hospital), investigated a rodent hepacivirus, RHV-rn1, that mimics human HCV infections in rats. This rat model served as a surrogate for the study of HCV persistence, immunity, and liver pathogenesis.
The team first sequenced and described the full RHV-rn1 genome, which had not been done previously. They cloned the consensus sequence of the complete genome to make a reverse genetic system and then injected laboratory strains of brown Norway rats with lab made RNA where they could produce infective virus. This process allowed access to unlimited and homogenous virus stocks for studies of infection, immunity and pathogenesis.
Trivedi et al. then explored the functional importance of two miR-122 binding sites, within the viral 5’ of the untranslated region. Several pools of random viral mutants were generated and inoculated in rats to identify virus mutants capable of infection and persistence in rats. These studies showed that one of the two miR-122 sites is indispensable for virus replication and persistence.
Trivedi et al. successfully developed and described a rodent hepacivirus system that directly translates to the human HCV system. Their results could allow optimization of effective vaccine designs to prevent hepacivirus persistence in natural settings. This research is a critical step to understanding and controlling HCV, which infects over 170 million people worldwide.
Synopsis written by Ellen Brandell
Image: Hepatitis C virus (Stanford Medicine)
Trivedi, Murthy, Sharma, Hartlage, Kumar, Gadi, Simmonds, Chauhan, Scheel, Billerbeck, Burbelo, Rice, Lipkin, Vandegrift, Cullen
Viral persistence, liver disease, and host response in a hepatitis C–like virus rat model