Hepatitis C virus cell entry: a target for novel antiviral strategies to address limitations of direct acting antivirals

Hepatitis C virus (HCV) infection remains a major global health problem, with 130-170 million chronically infected individuals at risk to develop severe liver disease, including hepatocellular carcinoma. Although the development of direct-acting antivirals offers cure for a large majority of patients, there are still a number of clinical challenges. These include DAA failure in a significant subset of patients, difficult-to-treat genotypes and limited access to therapy due to high costs. Moreover, recent data indicate that the risk for liver cancer persists in patients with advanced fibrosis. These challenges highlight the need for continued efforts towards novel therapeutic strategies for HCV. Over the past two decades, advances in HCV model systems have enabled a detailed understanding of HCV entry and its clinical impact. Many of the virus-host interactions involved in HCV entry have now been identified and explored as antiviral targets. Furthermore, viral entry is recognized as an important factor for graft reinfection and establishment of persistent infection. HCV entry inhibitors, therefore, offer promising opportunities to address the limitations of DAAs. Here, we summarize recent advances in the field of HCV entry and discuss perspectives towards the prevention and cure of HCV infection and virus-induced liver disease