Entry inhibitors: New advances in HCV treatment

Abstract

Hepatitis C virus (HCV) infection affects approximately 3% of the world's population and causes chronic liver diseases, including liver fibrosis, cirrhosis, and hepatocellular carcinoma. Although current antiviral therapy comprising direct-acting antivirals (DAAs) can achieve a quite satisfying sustained virological response (SVR) rate, it is still limited by viral resistance, long treatment duration, combined adverse reactions, and high costs. Moreover, the currently marketed antivirals fail to prevent graft reinfections in HCV patients who receive liver transplantations, probably due to the cell-to-cell transmission of the virus, which is also one of the main reasons behind treatment failure. HCV entry is a highly orchestrated process involving initial attachment and binding, post-binding interactions with host cell factors, internalization, and fusion between the virion and the host cell membrane. Together, these processes provide multiple novel and promising targets for antiviral therapy. Most entry inhibitors target host cell components with high genetic barriers and eliminate viral infection from the very beginning of the viral life cycle. In future, the addition of entry inhibitors to a combination of treatment regimens might optimize and widen the prevention and treatment of HCV infection. This review summarizes the molecular mechanisms and prospects of the current preclinical and clinical development of antiviral agents targeting HCV entry.

Figure 1

HCV entry into hepatocytes and antiviral agents targeting entry factors. The HCV lipoviral particle (LVP) is recruited and binds to glycosaminoglycans and low-density lipoprotein receptor on host cells. After binding, the virions interact with a series of entry factors. SRB1 plays a role in both binding and post-binding. CD81 interacts with HCV E2, forms a complex with claudin-1 (CLDN1), and mediates HCV movement to the tight-junction areas. This process is regulated by the receptor tyrosine kinase (RTK) family, including epidermal growth factor receptor (EGFR) and ephrin receptor A2 (EphA2). The virions internalize into host cells by clathrin-mediated endocytosis. Transferrin receptor 1 (TfR1) facilitates viral entry after CD81, possibly during HCV particle endocytosis. Niemann Pick C1-like 1 (NPC1L1) plays an important role in cholesterol transportation and is a cofactor for HCV entry during post-binding steps. Low pH-dependent membrane fusion between endosome and HCV particle. Red words and lines indicate the antiviral agents targeting different stages and factors of HCV entry.