Mechanisms of HCV internalization and fusion

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To multiply, viruses must deliver their genome into host cells. The critical step subsequently leading to viral replication is the penetration of the viral genome through a host cell membrane. Cell attachment of other members of the Flaviviridae family such as flaviviruses leads to endocytosis of bound virions (69). Clathrin-mediated endocytosis is the most commonly route of endocytosis for viruses that require internalization. It transports incoming viruses together with their receptors into early and late endosomes (6). It has been shown that early and late endosomes constitute distinct entry sites depending on the pH threshold of viral proteins. The acidic pH in endosomes provides an essential cue that triggers penetration and uncoating. Penetration of enveloped virus occurs by membrane fusion catalyzed by fusion peptides embedded in the viral envelope glycoproteins (70). In some cases, acidic pH is not sufficient to induce fusion and viral proteins need to be cleaved by endosomal proteases to become fusion competent. Two classes of viral fusion proteins (class I and II) mediating entry of enveloped viruses have been defined. Type II fusion proteins, occuring in flaviviruses and alpha viruses, are synthezised as heterodimers with other proteins that dissociate at the acidic pH in the endosome and assemble into more stable homotrimers that destabilizes the target cell membrane and then leads to the formation of a fusion pore (6, 71). Recent studies using HCVpp and HCVcc have demonstrated that HCV entry into both hepatoma cells and primary human hepatocytes depends on clathrin-mediated endocytosis (72-74). Structural homology with fusion proteins from flaviviruses suggests that HCV envelope glycoproteins may belong to class II fusions proteins (10, 75-77). Although – in contrast to flaviviruses- HCV glycoproteins are not matured by a cellular endoprotease during their transport through the secretory pathway (77), similar membrane fusion mechanisms may operate in HCV. This hypothesis is supported by the observation that HCVpp entry into Huh-7 cells is pH-dependent (17, 18, 78). In addition, HCVcc infection was markedly inhibited by agents preventing the acidification of endosomal compartments, suggesting that a pH-dependent membrane fusion process may be required for delivery of the HCV genome into the host cell cytosol (72, 79). Finally, it has been shown that HCVpp are delivered to early but not late endosomes (73). As HCV fusion kinetics are delayed as compared to other viruses, it has been suggested that after internalization, HCVpp entry necessitates additional, low-pH-dependent interactions, modifications, or trafficking (73). However, neither HCVpp nor HCVcc require cleavage by endosomal proteases for fusion (73, 79).