Figure 3.

Schematic representations of clathrin-mediated endocytosis and caveolin-mediated endocytosis. (A) HCV entry process illustrating the clathrin-mediated endocytosis. ①HCV binds GAGs (HS from syndecan-1 and syndecan-4) and LDLR, which have high affinity for the ApoE (apolipoprotein E). SRBI (scavenger receptor B type I) plays an important role in both binding and post-binding steps of viral entry through interaction with virion-associated lipoprotein or HCV E2. ②Binding of SRBI to HCV particles allows exposure of CD81 binding sites on HCV E2 and transfer of the virus particles to CD81. ③The virion is primed by the low-pH fusion activity of CD81 and CLDN1 and translocates to the tight junctions in order to be endocytosed. Viral internalization is dependent on clathrin-mediated endocytosis. Junction protein occludin (OCLN) can contribute to this process. TfR1, EGFR, and EphA2 (ephrin receptor A2) play a role in HCV infection at the level of glycoprotein-mediated entry, acts after CD81, and possibly are involved in the HCV particle internalization. PI3K-AKT and PI4K pathways are engaged in the late step of HCV entry. However, the molecular mechanisms need to be investigated. ④Following internalization, HCV fusion occurs in the early endosomes. Low pH environment and virion-associated cholesterol are required for the fusion process. NPC1L1 may play a role in this process via cholesterol transport. After fusion between the viral envelope and an endosomal membrane, the viral genome is released into the cytosol and replication takes place. Reprinted with permission from Zhu (2014). (B) SV40 entry process illustrating caveolin-mediated endocytosis. ①SV40 binding to the host cell is codirected by the capsid and VP2. ② The bound virus traverses the membrane and enters a caveolae. ③ The virus is endocytosed and transported in the caveolae-coated vesicles to endoplasmic reticulum.