Overview of HCV Life Cycle with a Special Focus on Current and Possible Future Antiviral Targets

Abstract

Hepatitis C infection is the leading cause of liver diseases worldwide and a major health concern that affects an estimated 3% of the global population. Novel therapies available since 2014 and 2017 are very efficient and the WHO considers HCV eradication possible by the year 2030. These treatments are based on the so-called direct acting antivirals (DAAs) that have been developed through research efforts by academia and industry since the 1990s. After a brief overview of the HCV life cycle, we describe here the functions of the different targets of current DAAs, the mode of action of these DAAs and potential future inhibitors.

Keywords: DAA; HCV; antiviral targets.

Figure 1

HCV lipoviroparticles and the virus life cycle. (a) HCV particles contain a positive strand RNA genome (in green) associated with Core proteins, enveloped by a membrane in which E1 and E2 glycoproteins are embedded and are tightly associated with lipids and apolipoproteins. (b) HCV life cycle. The different steps of HCV life cycle are indicated in black. ER Endoplasmic Reticulum. MW Membranous Web. LD Lipid Droplets. The negative strand replication intermediate in red.

Figure 2

HCV virus and replicon organization and membrane organization of the viral proteins. (a) The HCV genome is a positive strand RNA containing a single open-reading frame (from AUG to stop) surrounded by 5′ and 3′ highly structured non-translated regions (NTRs). Translation of the polyprotein is enhanced by miR-122 binding in the 5′NTR as indicated. Translation is initiated at the internal ribosomal entry site (IRES). The polyprotein is cleaved by cellular (white arrowheads) or viral (black arrowhead) proteases. C: Core protein. All Non-Structural (NS) proteins (including p7) are in black. (b) Example of organization of a HCV subgenomic replicon that were extensively used for antiviral drug screenings, they contain all the proteins necessary and sufficient for HCV RNA replication. Neomycin: Neomycin resistance gene. ECMV: Encephalomyocarditis Virus. (c) Membrane association of HCV proteins. Hatched bars represent amphipathic alpha helix or transmembrane domains anchoring the proteins to the membrane. Two examples of essential cellular proteins interacting with NS5A are shown. The three main types of inhibitors used in the clinic (indicated in red by their suffix) are indicated next to their target.