Naturally occurring antibodies recognizing linear epitopes in the amino-terminus of the hepatitis C virus E2 protein confer non-interfering, additive neutralization.

Chronic hepatitis C virus infection can persist even in the presence of a broadly neutralizing antibody response. Various mechanisms underpinning viral persistence have been proposed and one of the most recent is the presence of interfering antibodies that negate neutralizing responses. Specifically, it has been proposed that antibodies targeting broadly neutralizing epitopes located within a region of E2 encompassing residues 412-423 can be inhibited by non-neutralizing antibodies binding to a less conserved region encompassing residues 434-446. To investigate this phenomenon we characterized the neutralizing and inhibitory effects of human-derived affinity-purified immunoglobulin fractions and murine monoclonal antibodies and show that antibodies to both regions neutralize HCVpp and HCVcc virus infection, albeit with different breadth and potency. Epitope mapping revealed the presence of overlapping but distinct epitopes in both regions, which may explain the observed differences in neutralizing phenotype. Crucially, we failed to demonstrate any inhibition between these two groups of antibodies, suggesting that interference by non-neutralizing antibodies, at least to region 434-446, does not provide a mechanism for HCV persistence in chronically infected individuals.