Monoclonal antibodies with broad specificity for hepatitis C virus hypervariable region 1 variants can recognize viral particles

The hypervariable region 1 (HVR1) of the E2 protein of hepatitis C virus (H CV) is a highly heterogeneous sequence that is promiscuously recognized by human sera via binding to amino acid residues with conserved physicochemica l properties. We generated a panel of mAbs from mice immunized with HVR1 su rrogate peptides (mimotopes) affinity-selected with sera from HCV-infected patients from a phage display library. A high number of specific clones was obtained after immunization with a pool of nine mimotopes, and the resulti ng mAbs were shown to recognize several 16- and 27-mer peptides derived fro m natural HVR1 sequences isolated from patients with acute and chronic HCV infection, suggesting that HVR1 mimotopes were efficient antigenic and immu nogenic mimics of naturally occurring HCV variants. Moreover, most mAbs wer e shown to bind HVR1 in the context of a complete soluble form of the E2 gl ycoprotein, indicating recognition of correctly folded HVR1. In addition, a highly promiscuous mAb was able to specifically capture bona fide viral pa rticles (circulating HCV RNA) as well as rHCV-like particles assembled in i nsect cells expressing structural viral polypeptides derived from an HCV la isolate. These findings demonstrate that it is possible to induce a broadl y cross-reactive clonal Ab response to multiple HCV variants. In considerat ion of the potentially important role of HVR1 in virus binding to cellular receptor(s), such a mechanism could be exploited for induction of neutraliz ing Abs specific for a large repertoire of viral variants.