Host-Targeting Agents to Prevent and Cure Hepatitis C Virus Infection

Abstract

Chronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma (HCC) which are leading indications of liver transplantation (LT). To date, there is no vaccine to prevent HCV infection and LT is invariably followed by infection of the liver graft. Within the past years, direct-acting antivirals (DAAs) have had a major impact on the management of chronic hepatitis C, which has become a curable disease in the majority of DAA-treated patients. In contrast to DAAs that target viral proteins, host-targeting agents (HTAs) interfere with cellular factors involved in the viral life cycle. By acting through a complementary mechanism of action and by exhibiting a generally higher barrier to resistance, HTAs offer a prospective option to prevent and treat viral resistance. Indeed, given their complementary mechanism of action, HTAs and DAAs can act in a synergistic manner to reduce viral loads. This review summarizes the different classes of HTAs against HCV infection that are in preclinical or clinical development and highlights their potential to prevent HCV infection, e.g., following LT, and to tailor combination treatments to cure chronic HCV infection.

Keywords: direct-acting antiviral; hepatitis C virus; host-targeting agent; viral resistance.

Figure 1

Schematic representation of the hepatitis C virus (HCV) life cycle and targets for antiviral therapy. HCV interacts with the basolateral membrane of hepatocytes, resulting in viral entry into the host cell. The virus is internalized via endocytosis and translation of the HCV RNA occurs in the cytoplasm following viral fusion and uncoating. Viral replication takes place within the cytoplasm in perinuclear endoplasmic reticulum (ER)-derived membranes called the “membranous web”. Progeny virions are assembled on cytosolic lipid droplets and subsequently transported along the secretory pathway and maturated in the Golgi before their release through microtubular transport and endocytic recycling compartment. Targets for antiviral therapy are highlighted in red.

Figure 2

Schematic representation of HCV entry. The initial viral attachment on the basolateral membrane of hepatocytes is believed to involve the interaction of the viral particle—both viral (HCV envelope glycoproteins) and host-derived (apolipoproteins) factors—with HSPGs (heparan sulfate proteoglycans), LDLR (low density lipoprotein receptor) and SR-BI (scavenger receptor class B type I). Following interaction between the virus and different host factors expressed at the hepatocyte cell surface, including CD81 (cluster of differentiation 81) and CLDN1 (claudin 1), as well as rearrangement of cell surface proteins, the virus is ultimately internalized into its host cell via clathrin-mediated endocytosis. Additional host factors, including EGFR (epidermal growth factor receptor), NPC1L1 (Niemann-Pick C1-like 1) and TfR1 (transferrin receptor 1), contribute to the HCV entry process, for example by modulating intracellular signaling pathways or endocytosis. Following acidification of the endosome and subsequent fusion of viral and endosomal membranes, the viral genome is released into the cytoplasm. In addition to cell-free virus entry, HCV has also been described to transmit between hepatocytes through direct cell-to-cell transmission involving CD81, SR-BI, CLDN1, OCLN (occludin), EGFR, EphA2 (ephrin receptor A2) and NPC1L1. HTAs can interfere with different steps of the HCV entry process as highlighted in red.

Figure 3

Schematic representation of HCV assembly. Virion assembly is triggered by core recruitment on cytosolic lipid droplets (cLDs) by the diacylglycerol acyltransferase-1 (DGAT-1). In turn, replication complexes are recruited through core-NS5A interactions. Nucleocapsid formation is mediated by viral budding into the ER lumen, at the site of VLDL production. The immature viral particles fuse or attach to a luminal LD (LuLD) through apoE-E1E2 and apoE-NS5A interactions. During VLDL synthesis, apolipoprotein B (apoB) is directly produced in the ER lumen and enriched in lipids by the microsomal triglyceride transfer protein (MTP) to generate VLDL precursors. Viral particles merge with these nascent VLDLs to generate mature lipoviroparticles (LVPs). LVPs enter the VLDL maturation and secretion pathway to be released from hepatocytes. HCV assembly and egress can be impaired by targeting different steps of these processes as highlighted in red.

Figure 4

Synergy between HTAs and DAAs to inhibit HCV infection at different steps of the viral life cycle. Given their complementary mechanism of action, HTAs and DAAs can act in a synergistic manner to reduce viral loads and to prevent viral resistance. Different classes of HTAs and DAAs that have been evaluated in combination are highlighted in red.