Broadly cross-reactive, high-affinity antibody to hypervariable region 1 of the hepatitis C virus in rabbits

The HCV hypervariable region 1 (HVR1) of the main E2 envelope protein is critically important in HCV neutralization but its extreme variability makes immune therapy and vaccine development particularly difficult. To explore the hypothesis that HVR1 carries a common epitope susceptible of eliciting cross-reactive neutralizing and inhibitory antibodies, rabbits were immunized with a series of synthetic HVR1 peptides. The anti-HVR1 produced were purified and characterized. Several lines of evidence supported the working hypothesis: (1) although injected only once, a boosting effect from poorly homologous peptides was observed; (2) purified rabbit IgG reacted with high affinity with immunizing peptides and cross-reacted with 16 of 17 unrelated HVR1 peptides; (3) antibodies appeared of restricted diversity irrespective of the linear HVR1 peptide sequences; (4) anti-HVR1 peptides effectively captured HCV in 22 of 33 plasmas from random infected patients; (5) anti-HVR1 IgG blocked the binding of antibody-captured HCV to MOLT-4 cells. These findings suggest that with an appropriate HVR1 peptide immunization scheme, high titer, broadly cross-reactive, blocking antibodies to HCV can be produced. Antibodies to the putative ubiquitous HVR1 epitope may have important clinical uses.