Hepatitis C virus envelope protein dynamics and the link to hypervariable region 1

Conformational dynamics of viral envelope proteins seem to be involved in mediating evasion from neutralizing antibodies (NAbs) by mechanisms that limit exposure of conserved protein motifs. For hepatitis C virus (HCV), molecular studies have only recently begun to unveil how such dynamics of the envelope protein heterodimer, E1/E2, are linked to viral entry and NAb evasion. Here, we review data suggesting that E1/E2 exists in an equilibrium between theoretical 'open' (NAb-sensitive) and 'closed' (NAb-resistant) conformational states. We describe how this equilibrium is influenced by viral sequence polymorphisms and that it is critically dependent on the N-terminal region of E2, termed hypervariable region 1 (HVR1). Finally, we discuss how it appears that the virus binding site for the HCV entry co-receptor CD81 is less available in 'closed' E1/E2 states and that NAb-resistant viruses require a more intricate entry pathway involving also the entry co-receptor, SR-BI.