TOWARDS A SOLUTION FOR HEPATITIS-C VIRUS HYPERVARIABILITY - MIMOTOPESOF THE HYPERVARIABLE REGION-1 CAN INDUCE ANTIBODIES CROSS-REACTING WITH A LARGE NUMBER OF VIRAL VARIANTS

The hypervariable region 1 (HVR1) of the putative envelope protein E2 of hepatitis C virus (HCV) is the most variable antigenic fragment in the whole viral genome and is mainly responsible for the large inter- and intra-individual heterogeneity of the infecting virus. It contains a principal neutralization epitope and has been proposed as the major player in the mechanism of escape from host immune response. Since an ti-HVR1 antibodies are the only species shown to possess protective ac tivity up to date, developing an effective prevention therapy is a ver y difficult task. We have approached the problem of HVR1 variability b y deriving a consensus profile from >200 HVR1 sequences from different viral isolates and used it as a template to generate a vast repertoir e of synthetic HVR1 surrogates displayed on M13 bacteriophage. This li brary was affinity selected using many different sera from infected pa tients. Phages were identified which react very frequently with patien ts' sera and bind serum antibodies that cross-react with a large panel of HVR1 peptides derived from natural HCV variants. When injected int o experimental animals, the 'mimotopes' with the highest cross-reactiv ity induced antibodies which recognized the same panel of natural HVR1 variants, In these mimotopes we identified a sequence pattern respons ible for the observed crossreactivity, These data may hold the key for future development of a prophylactic vaccine against HCV.