Hepatitis C virus entry: An intriguing challenge for drug discovery

The entry of hepatitis C virus (HCV) into host cells is an obligatory step in virus replication that presents a multi-faceted opportunity for drug discovery. However, the current understanding of HCV entry is rudimentary at best, with insights to date obtained by examining the fusion of pseudoparticles that express the HCV surface glycoproteins E1 and E2. The absence of an infectious virus replication system capable of replicating through a full virus life-cycle has hampered progress in determining the events involved in viral entry, resulting in considerable ambiguity surrounding the process. The recent development of an infectious HCV virus replication system provides a method with which to examine HCV entry in detail in a setting that promises greater authenticity and with the potential to increase understanding of this process. Weak inhibitors of the interactions between the HCV glycoproteins and potential host cell receptors have been identified, but their mechanism of action, in the context of virus infectivity, is not understood, and these inhibitors remain to be validated with infectious virus in cell culture. The advent of an infectious virus replication system holds considerable promise for developing a detailed understanding of HCV entry, but while mechanistic insights developed with other viruses may provide useful paradigms for experimental design, it is likely that HCV entry will be characterized by several unique biochemical events. Developing a deeper understanding of HCV entry will clearly take some time given the complexity of the process and the current state of affairs. Nevertheless, interfering with HCV entry holds promise for drug design and discovery as the mechanistic insights emerge and coalesce into a coherent biochemical description of the process.