The hepatitis C virus (HCV) glycoprotein E2 is present on the virion surface and is one of the major targets of antibodies in HCV infection. The N-terminal hypervariable region 1, HVR1 (384-408) is an immunodominant region within E2 and elicits type specific neutralizing antibodies. In addition, studies have demonstrated that HVR1 is likely to be highly flexible and reduces the activity of neutralizing antibodies to the E2 core domain. However, HVR1 is known to play an essential role in binding of infectious serum derived HCV particles to scavenger receptor class B type 1 and glycosaminoglycans on the cell surface that are essential stages in HCV entry. Cross neutralizing antibodies towards HVR1 have not been characterised in detail and there is no structural data available for HVR1..
We have identified a novel rodent monoclonal antibody, MAb33, that binds to an unusual epitope that bridges HVR1 and the adjacent target of broadly neutralizing antibodies referred to as epitope I (408-423). Monoclonal antibody 33 displays the ability to cross-neutralize 4 different HCV genotypes and blocks the interaction between E2 and its cellular receptor CD81. Alanine scanning mutagenesis will define the residues involved in recognition by MAb33 and structural studies involving the antigen binding fragment and a synthetic peptide will be used to provide structural information for the HVR1 region for the first time. The results of this study will provide novel insight into the structure of HCV E2 and properties of antibodies directed towards HVR1. Understanding the properties of this region and neutralizing antibodies targeting this region will help inform HCV vaccine development and our understanding of immunoprotection from HCV.