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. 2008 Mar;89(Pt 3):653-659.
doi: 10.1099/vir.0.83386-0.

Broadly neutralizing human monoclonal antibodies to the hepatitis C virus E2 glycoprotein

Ania M Owsianka  1 , Alexander W Tarr  2 , Zhen-Yong Keck  3 , Ta-Kai Li  3 , Jeroen Witteveldt  1 , Richard Adair  1 , Steven K H Foung  3 , Jonathan K Ball  2 , Arvind H Patel  1
Affiliations

Broadly neutralizing human monoclonal antibodies to the hepatitis C virus E2 glycoprotein

Ania M Owsianka et al. J Gen Virol. 2008 Mar.

Abstract

The humoral response to hepatitis C virus (HCV) may contribute to controlling infection. We previously isolated human monoclonal antibodies to conformational epitopes on the HCV E2 glycoprotein. Here, we report on their ability to inhibit infection by retroviral pseudoparticles incorporating a panel of full-length E1E2 clones representing the full spectrum of genotypes 1-6. We identified one antibody, CBH-5, that was capable of neutralizing every genotype tested. It also potently inhibited chimeric cell culture-infectious HCV, which had genotype 2b envelope proteins in a genotype 2a (JFH-1) background. Analysis using a panel of alanine-substitution mutants of HCV E2 revealed that the epitope of CBH-5 includes amino acid residues that are required for binding of E2 to CD81, a cellular receptor essential for virus entry. This suggests that CBH-5 inhibits HCV infection by competing directly with CD81 for a binding site on E2.

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Figures

Fig. 1.
Fig. 1.
(a) Neutralization by HmAbs of HCVpp pseudotyped with E1E2 sequences of genotypes 1–6. This dataset is representative of results obtained in at least three independent experiments. (b) Reactivity of HmAbs CBH-2 (•), CBH-5 (○) and CBH-7 (▾) with purified HCVpp in GNA ELISA. The following E1E2 sequences were used: genotype 1a, H77c (GenBank accession no. AF011751) and H (Bartosch et al., 2003b; Helle et al., 2007); genotype 1b, UKN1B5.23 (AY734976); genotype 2a, UKN2A1.2 (AY734977); genotype 2b, UKN 2B1.1 (AY734982); genotype 3a, UKN3A13.6 (AY894683); genotype 4, UKN4.11.1 (AY734986); genotype 5, UKN5.15.11 (AY894682); genotype 6, UKN6.5.8 (EF427671).
Fig. 2.
Fig. 2.
Neutralization by HmAbs CBH-2 (•), CBH-5 (○) and CBH-7 (▾) of (a) genotype 2b HCVcc and (b) genotype 2b HCVpp. (c) IC50 and IC90 of each HmAb for genotype 2b HCVcc and HCVpp.
Fig. 3.
Fig. 3.
Alanine-replacement mutagenesis. Mutant proteins are annotated according to the amino acid in the H77c sequence, the amino acid position relative to the start of the H77 polyprotein chain and the substitution introduced. Binding of antibody to each mutant protein is expressed as a percentage of binding to wild-type H77c protein.
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