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. Author manuscript; available in PMC: 2018 Sep 15.
Published in final edited form as: Expert Rev Proteomics. 2017 Jun 30;14(7):593–606. doi: 10.1080/14789450.2017.1344102

Figure 5: Overview of HCV life cycle and role of apolipoproteins in HCV entry and morphogenesis. (A) HCV life cycle is divided into 7 main steps.

Figure 5:

(1) LVP are captured by attachment factors at the hepatocyte surface. (2) Then, HCV enters the cells by interacting with several host factors. (3) After clathrin mediated-endocytosis and membrane fusion, viral RNA is release in cytoplasm. (4) Viral polyprotein is generated by an IRES-mediated translation. This polyprotein is maturated by viral and host proteases into 7 viral proteins. (5) Non-structural viral proteins form RNA replication complex in a particular web of ER- derived membranes named “membranous web” (MW). (6) After RNA replication, viral particles are assembled in MW in close proximity with lipid droplet (LD). (7) Finally, viral particles interact with VLDL to form an infectious LVP that is maturated and excreted through the VLDL secretion pathway. (B) HCV entry pathway. (1) Viral particle attachment is mediated by LVP-associated ApoE through interaction with HSPG, LDLR and SR-BI. (2) Then HCV interacts with CD81 and SR-BI through E2. The lipid-transfer activity of SR-BI seems to destabilize the VLDL-HCV interaction to induce E2 binding on cell receptors and HCV entry. ApoC-I facilitates this step (not illustrated). Binding on CD81 induces EGFR signaling pathway activation and interaction between CD81 and CLDN1 that triggers HCV entry. (3) Viral particle is internalized through a clathrin-dependent endocytosis. (4) Viral envelope and vesicle membrane fuse to induce viral RNA release in cytoplasm. OCLDN and NPC1L1 illustrated in this picture are co-factors involved in HCV entry. (C) HCV assembly pathway. (1) HCV particle assembly is triggered by Core protein trafficking from cytosolic LD (cLD), to assembly site. Core then associated with viral RNA to form nuleocapsids. These two steps are facilitated by non-structural proteins (illustrated on the scheme) and several host factors. (2) The nascent HCV particles bud at ER-surface where E1 and E2 proteins are anchored. (3) In parallel, ApoB is translocated into ER lumen and lipidated by MTP to generate VLDL precursor. VLDL precursor, luminal LD (luLD) associated with ApoE and ApoC and nascent HCV particles are then associated through an unknown mechanism to generate mature LVP (4). Interaction between NS5A and LD-associated ApoE but also between ApoE and viral glycoproteins are involved in this process.