Mechanisms of HCV resistance to broadly neutralizing antibodies

Broadly neutralizing antibodies (bNAbs) block infection by genetically diverse hepatitis C virus (HCV) isolates by targeting relatively conserved epitopes on the HCV envelope glycoproteins, E1 and E2. Many amino acid substitutions conferring resistance to these bNAbs have been characterized, identifying multiple mechanisms of bNAb escape. Some resistance substitutions follow the expected mechanism of directly disrupting targeted epitopes. Interestingly, other resistance substitutions fall in E2 domains distant from bNAb-targeted epitopes. These substitutions, which can confer broad resistance to multiple bNAbs, act by less clearly defined mechanisms. Some modulate binding of HCV to cell surface receptors, while others may induce conformational changes in the E2 protein. In this review, we discuss mechanisms of HCV bNAb resistance and implications for HCV vaccine development.