The hepatitis C virus glycan shield and evasion of the humoral immune response

Abstract

Despite the induction of effective immune responses, 80% of hepatitis C virus (HCV)-infected individuals progress from acute to chronic hepatitis. In contrast to the cellular immune response, the role of the humoral immune response in HCV clearance is still subject to debate. Indeed, HCV escapes neutralizing antibodies in chronically infected patients and reinfection has been described in human and chimpanzee. Studies of antibody-mediated HCV neutralization have long been hampered by the lack of cell-culture-derived virus and the absence of a small animal model. However, the development of surrogate models and recent progress in HCV propagation in vitro now enable robust neutralization assays to be performed. These advances are beginning to shed some light on the mechanisms of HCV neutralization. This review summarizes the current state of knowledge of the viral targets of anti-HCV-neutralizing antibodies and the mechanisms that enable HCV to evade the humoral immune response. The recent description of the HCV glycan shield that reduces the immunogenicity of envelope proteins and masks conserved neutralizing epitopes at their surface constitutes the major focus of this review.

Keywords: N-glycosylation; hepatitis C virus; neutralizing antibodies; viral escape.

Figure 1.

Localization of the N-linked glycans on the model of hepatitis C virus (HCV) E2 glycoprotein (modified version of the figure published by Helle et al. [28], adapted from the model recently published by Krey et al. [37]). The linear sequence of the JFH-1 strain E2 ectodomain without the stem region is represented as a chain of beads (colored circles) labeled with the corresponding amino acid and threaded onto a class II fold. The three putative domains are presented in red (DI), yellow (DII), and blue (DIII), and the variable regions (HVR1, HVR2, and IgVR) are indicated in brown. Circles in pale and bright colors represent residues in the background and foreground of the domains, respectively. Disulfide bonds are indicated by black bars. DI domain residues that are involved in CD81 binding [48] are outlined in blue. Amino acids recognized by known anti-HCV monoclonal neutralizing antibodies (NAbs) (Table 1) are shown as grey circles. Glycosylation sites are shown as sequentially-numbered green circles. Glycosylation sites masking the CD81 binding site are highlighted with light green shading.