Globally, more than 150 million people are infected with hepatitis C virus (HCV) including about 20 thousand in Denmark. There are 3-4 million new infections per year, and the majority of acutely infected individuals develop chronic hepatitis. Chronically infected individuals have a ~20% risk for developing liver cirrhosis, and 1–5% per year will subsequently develop liver cancer. Overall, about 500 thousand deaths per year are attributed to HCV induced end-stage liver disease.
Hepatitis C virus is an enveloped virus with a positive single-strand RNA genome, classified within the Flaviviridae family of viruses. It is thus related to other important human pathogens, including Yellow Fever and West Nile viruses. HCV exhibits extensive genetic heterogeneity, and isolates are classified into 7 major genotypes and more than 50 subtypes, differing in ~30% and ~20% of their genome sequences, respectively. Different genotypes and subtypes vary in their susceptibility to antiviral therapy, including direct acting antiviral regimens that will most likely become the new standard of care.
Genetic diversity has been an obstacle for the development of effective therapies, as well as for vaccine development.
Research in CO-HEP focuses on basic studies of the hepatitis C virus life cycle with special emphasis on the importance of the virus heterogeneity. We aim to develop novel infectious culture systems of HCV genotypes 1-7 through viral mutations-driven adaptation process.
We aim at defining the molecular mechanisms of adaptive mutations to unravel the viral-host interactions involved. Beyond developing such relevant culture systems, we will use them to determine the function of identified key adaptive mutations in promoting in vitro replication of patient isolates with the perspective of developing culture conditions and cell lines that will support HCV in vitro studies more universally. We will use the developed viruses to perform novel studies of HCV antiviral sensitivity and resistance in different genotypes, thus advancing therapy.
A main objective is to unravel the molecular mechanism of drug escape in HCV by understanding the role of resistance mutations evolving in vitro and in vivo. The developed HCV infectious cell culture systems will permit detailed functional analysis of HCV genome regions and proteins, including genetic recombination studies. Finally, a main objective is to utilize developed recombinant technology and the infectious culture systems to develop vaccine candidates against HCV.