Humoral immune system targets clonotypic antibody associated Hepatitis C Virus.

Hypervariable region 1 (HVR1) is one of the potential neutralisation domains in the E2 glycoprotein of Hepatitis C virus (HCV). Point mutations of the HVR1 can lead to humoral immune escape in HCV infected patients. In this study we segregated the chronically infected viraemic sera from HCV infected patients into populations of antibody free virus (AFV) and antibody associated virus (AAV) and mapped potential epitopes within the E1E2 gene junction of AAV sequences (residues 364-430). Furthermore, we generated pseudotyped HCV particles (HCVpp) derived from AAV sequence to assess their infectivity. We studied the neutralisation potential of virus free Fab (VF-Fab) obtained from antibody-virus complexes, in the HCVpp system. We observed selective targeting of clonotypic HCV variants from the quasispecies pool. Moreover, we identified potential neutralising epitopes within the HVR1 and an additional epitope which overlapped with a broadly neutralising AP33 epitope (amino acid 412-423 in E2). We observed a marked difference in the infectivity of HCVpp generated using E1E2 sequences isolated from AAV. We document reduction in the infectivity of HCVpp H77 and HCVpp derived from AAV sequence when challenged with VF-Fab. Our results provide novel insights into the complexities of engagement between HCV and the humoral immune system.