PMC

HCV envelope glycoprotein 2 surface representation. E2 is a globular protein with three regions of hypervariablity – HVR1, HVR2, and intergenotypic variable region – shown in green. Domains whose structures are currently unknown are depicted as shapes apart from the structure. HVR1 is predicted to mask a hydrophobic region that is sensitive to nAbs. E2’s broadly neutralizing face, where many broadly neutralizing Abs bind, comprises CD81-binding loop (in red), residues 421–453 (in orange), residues 502–520 (in pink), and residues 412–421 (in purple). The possible positions of some glycans are shown as stick and ball figures. E2 structure obtained from PDB (4MWF) ().

Mechanisms of HCV evasion of the humoral immune system. HCV has developed several strategies for evading the humoral immune system. (A) A high rate of replication using a polymerase that lacks any proofreading mechanism leads to generation of a rapidly changing quasispecies. (B) The highly immunogenic HVR1 masks a hydrophobic region that is sensitive to nAbs. (C) E2 is heavily glycosylated, containing between 9 and 11 N-linked glycans (in green) that mask much of the surface of E2 from nAbs. (D) The close association between HCV and lipoprotein effectively conceals the lipoviral particle from nAbs. (E) HCV may bypass the extracellular space and nAbs by spreading cell-to-cell. (F) Interfering antibodies can disrupt the action of nAbs by binding to non-neutralizing sites and masking neutralizing sites nearby.