Mechanisms of HCV resistance to broadly neutralizing antibodies

Abstract

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.

Figure 1.

Location of resistance substitutions on the E2 ectodomain structure [PDB 6MEI] [39]. E2 is gray, with the front layer (aa 424–459) and CD81 binding loop (aa 519–535) shaded in pink and AS412 (aa 412–423) shaded in light blue. Location of substitutions conferring resistance to (i) bNAbs targeting front layer/CD81 binding loop (red), (ii) bNAbs targeting AS412 (blue), or (iii) multiple bNAbs targeting distinct antigenic sites (green) are displayed on the surface of E2. V506 (front layer bNAb resistance) is not visible because it is buried within the structure. Positions of resistance substitutions for E1E2 complex bNAbs (L665, I696) as well some substitutions conferring resistance to multiple bNAbs (V400, G401, L403, T404) are not shown because they are truncated or unresolved in the crystal structure.