The neutralizing activity of anti-hepatitis C virus antibodies is modulated by specific glycans on the E2 envelope protein.
Hepatitis C virus (HCV) envelope glycoproteins are highly glycosylated, with up to 5 and 11 N-linked glycans on E1 and E2, respectively. Most of the glycosylation sites on HCV envelope glycoproteins are conserved, and some of the glycans associated with these proteins have been shown to play an essential role in protein folding and HCV entry. Such a high level of glycosylation suggests that these glycans can limit the immunogenicity of HCV envelope proteins and restrict the binding of some antibodies to their epitopes. Here, we investigated whether these glycans can modulate the neutralizing activity of anti-HCV antibodies. HCV pseudoparticles (HCVpp) bearing wild-type glycoproteins or mutants at individual glycosylation sites were evaluated for their sensitivity to neutralization by antibodies from the sera of infected patients and anti-E2 monoclonal antibodies. While we did not find any evidence that N-linked glycans of E1 contribute to the masking of neutralizing epitopes, our data demonstrate that at least three glycans on E2 (denoted E2N1, E2N6, and E2N11) reduce the sensitivity of HCVpp to antibody neutralization. Importantly, these three glycans also reduced the access of CD81 to its E2 binding site, as shown by using a soluble form of the extracellular loop of CD81 in inhibition of entry. These data suggest that glycans E2N1, E2N6, and E2N11 are close to the binding site of CD81 and modulate both CD81 and neutralizing antibody binding to E2. In conclusion, this work indicates that HCV glycans contribute to the evasion of HCV from the humoral immune response.
Helle
François
F
Institut de Biologie de Lille (UMR8161), CNRS, Université Lille I and II and Institut Pasteur de Lille, Lille, France.
Goffard
Anne
A
Morel
Virginie
V
Duverlie
Gilles
G
McKeating
Jane
J
Keck
Zhen-Yong
ZY
Foung
Steven
S
Penin
François
F
Dubuisson
Jean
J
Voisset
Cécile
C
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000276:immunology; D000939:Epitopes; D006031:Glycosylation; D016174:Hepacivirus / Q000737:chemistry / Q000276:immunology*; D006526:Hepatitis C; D018937:Hepatitis C Antibodies / Q000276:immunology*; D006801:Humans; D011134:Polysaccharides / Q000737:chemistry / Q000276:immunology*; D014759:Viral Envelope Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000939:Epitopes; D018937:Hepatitis C Antibodies; D011134:Polysaccharides; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus