Abstract
Despite 20 years of research, a vaccine to prevent hepatitis C virus (HCV) infection has not been developed. A vaccine to prevent HCV will need to induce broadly reactive immunity able to prevent infection by the 7 genetically and antigenically distinct genotypes circulating world-wide. HCV encodes two surface exposed glycoproteins, E1 and E2 that function as a heterodimer to mediate viral entry. Neutralizing antibodies (NAbs) to both E1 and E2 have been described with the major NAb target being E2. The function of E2 is to attach virions to host cells via cell surface receptors that include, but is not limited to, the tetraspanin CD81 and scavenger receptor class B type 1. However, E2 has developed a number of immune evasion strategies to limit the effectiveness of the NAb response and possibly limit the ability of the immune system to generate potent NAbs in natural infection. Hypervariable regions that shield the underlying core domain, subdominant neutralization epitopes and glycan shielding combine to make E2 a difficult target for the immune system. This review summarizes recent information on the role of NAbs to prevent HCV infection, the targets of the NAb response and structural information on glycoprotein E2 in complex with neutralizing antibodies. This new information should provide a framework for the rational design of new vaccine candidates that elicit highly potent broadly reactive NAbs to prevent HCV infection.
Highlights
ARTICLE The most cost effective means of controlling infectious disease is through vaccination, a prophylactic or therapeutic vaccine for hepatitis C virus (HCV) is not available
E2 has developed a number of immune evasion strategies to limit the effectiveness of the Neutralizing antibodies (NAbs) response and possibly limit the ability of the immune system to generate potent NAbs in natural infection
This review summarizes recent information on the role of NAbs to prevent HCV infection, the targets of the NAb response and structural information on glycoprotein E2 in complex with neutralizing antibodies
Summary
1998; Scarselli et al, 2002). The functional properties of E1/E2 and the ability of E1/E2-specific antibodies to prevent viral entry can be studied using retroviruses pseudotyped with E1/E2 (HCVpp; Bartosch et al, 2003; Drummer et al, 2003; Hsu et al, 2003) or cell culture derived HCV (HCVcc) made by transfecting full-length HCV RNA into Huh 7 cells (Lindenbach et al, 2005; Wakita et al, 2005; Yi et al, 2006). The binding site for CD81, the major cellular receptor for all HCV strains, comprises highly conserved segments within the E2 RBD (Drummer et al, 2002; Roccasecca et al, 2003; Zhang et al, 2004; Drummer et al, 2006; Owsianka et al, 2006; Figure 1A) These regions of E2 interact with the large extracellular loop (LEL) of CD81 through Ile182, Asn184, Phe186, and Leu162 on the head subdomain (Higginbottom et al, 2000; Drummer et al, 2002). 461–481) flanked by conserved cysteine residues that form a surface exposed disulfide bonded loop, not essential for folding of the E2 RBD core (McCaffrey et al, 2007; Kong et al, 2013). The igVR is within a flexible region spanning 567–596 and the back layer is formed by two short α-helices and 4 β sheets
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