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HCV has chronically infected an estimated number of 160 million individuals worldwide.1 In the course of 10–20 years of persistent infection, approximately 20% of these patients are at risk of developing severe liver disease, including fibrosis, cirrhosis and hepatocellular carcinoma.2 Besides the ability to establish chronic infection, the pronounced genetic variability of HCV and the diverse course of chronic infection ranging from relatively benign to exacerbating liver disease are hallmarks of hepatitis C. Moreover, response to classical antiviral treatment based on pegylated interferon alpha (PEG-IFN-α) and ribavirin is substantially influenced by viral and host factors, since viral genotypes 1 and 4 are more resilient to therapy compared with genotypes 2 and 3 and as polymorphisms in the vicinity of the IFN28B locus predict the chances to naturally clear HCV infection and of response to IFN-based therapies.3 ,4 The high degree of virus variability is also a formidable challenge in the emerging era of directly acting antivirals for treatment of hepatitis C by mediating drug escape through resistance mutations. Moreover, many molecules, most prominently the already licensed protease inhibitors telaprevir and boceprevir, display a genotype-dependent antiviral activity. Therefore, both viral and host genetic variability complicate provision of efficacious, safe, well-tolerated and cost-effective therapies to the large number of HCV patients.
At the same time, HCV has been resistant to disclosing its secrets as the road for development of suitable cell culture and animal models to dissect mechanism of virus replication and liver disease has been paved with many roadblocks. For instance, infection of cultured cells by primary patient-derived virus from sera …
Funding TP is supported by grants from the Deutsche Forschungsgemeinschaft (SFB 900, project A6) and (PI 734/2–1) by grants from the Helmholtz Association (SO-024, HAI-IDR) and by a grant from the European Research Council (ERC-2011-StG_281473-VIRAFRONT).
Competing interests None.
Provenance and peer review Commissioned; internally peer reviewed.