Hepatitis C Virus Epitope Immunodominance and B Cell Repertoire Diversity

Abstract

Despite the advent of effective, curative treatments for hepatitis C virus (HCV), a preventative vaccine remains essential for the global elimination of HCV. It is now clear that the induction of broadly neutralising antibodies (bNAbs) is essential for the rational design of such a vaccine. This review details the current understanding of epitopes on the HCV envelope, characterising the potency, breadth and immunodominance of antibodies induced against these epitopes, as well as describing the interactions between B-cell receptors and HCV infection, with a particular focus on bNAb heavy and light chain variable gene usage. Additionally, we consider the importance of a public repertoire for antibodies against HCV, compiling current knowledge and suggesting that further research in this area may be critical to the rational design of an effective HCV vaccine.

Characterization of antibody‐dependent cellular phagocytosis in patients infected with hepatitis C virus with different clinical outcomes

“…The HCV envelope protein E1E2 with the different domains (Dom) and/or antigenic regions (AR) targeted by specific monoclonal antibodies used for epitope mapping of plasma anti‐E2 antibodies produced by patients is shown in Figure 6A for reference 30 . A statistical correlation matrix showed that antibodies in patient plasma targeting E2 Domain B (AR3A) and Domain D (HC84.26) had a significant positive relationship with high phagocytosis with r scores of 0.64 ( p = 0.0001) and 0.51 ( p = 0.0003), respectively, as contrasted to the significant negative relationships observed between high phagocytosis and antibodies targeting E2 Domain E (HCV1) and Domain C (CBH‐7) with r scores of −0.38 ( p = 0.008) and −0.36 ( p = 0.0003), respectively, (Figure 6B).…”

“…The HCV envelope protein E1E2 with the different domains (Dom) and/or antigenic regions (AR) targeted by specific monoclonal antibodies used for epitope mapping of plasma anti‐E2 antibodies produced by patients is shown in Figure 6A for reference. 30 A statistical correlation matrix showed that antibodies in patient plasma targeting E2 Domain B (AR3A) and Domain D (HC84.26) had a significant positive relationship with high phagocytosis with r scores of 0.64 ( p = 0.0001) and 0.51 ( p = 0.0003), respectively, as contrasted to the significant negative relationships observed between high phagocytosis and antibodies targeting E2 Domain E (HCV1) and Domain C (CBH‐7) with r scores of −0.38 ( p = 0.008) and −0.36 ( p = 0.0003), respectively, (Figure 6B ). Interestingly, antibodies targeting Domains B and D had also a significant positive association to neutralization function with r scores of 0.65 ( p = 0.0001) and 0.53 ( p = 0.0004), respectively, while those targeting Domains E ( r = −0.33; p = 0.03) and Domain C ( r = −0.58; p = 0.0004) had significant negative associations, suggesting functional overlap between ADCP and neutralization (Figure 6C ).…”

“… Epitope mapping and parameter matrices of the associative relationship of ADCP to multiple independent variables. Schematic illustration of the HCV envelope protein E2 with the different Domains (Dom) and/or antigenic regions (AR) targeted by specific monoclonal antibodies used for epitope mapping of plasma anti‐E2 antibodies produced by patients: Domain A (red; mAb CBH4G), Domain B (green; mAb AR3A), Domain C (pink; mAb CBH7), Domain D (blue; mAb HC84.26), Domain E (yellow; mAb HCV1), region AR1 (cyan; mAb AR1B), region AR2 (orange; mAb AR2A), region AR4/5 (black; mAb AR4/5 A) 30 (A). A heatmap of a parameter correlation matrix between ADCP and the different E2 epitopes targeted by antibodies in patient plasma shows that antibodies targeting Domain B (AR3A) and Domain D (HC84.26) had a significant positive relationship with high phagocytosis with r scores of 0.64 ( p = 0.0001) and 0.51 ( p = 0.0003), respectively as contrasted to the significant negative relationships observed with antibodies targeting Domain E (HCV1) and Domain C (CBH‐7) with r scores of −0.38 ( p = 0.008) and −0.36 ( p = 0.0003) respectively (B).…”

“…An epitope is a certain sequence of amino acids on a pathogen that allows for specific binding of a given antibody. In HCV infection, several neutralizing antibodies have been identified to target specific epitopes on certain antigenic regions or domains of the E2 protein (Antigenic Regions 1–5; also known as Domains A–E or Epitopes I–III), although some are found to target conformational epitopes made up of both E1 and E2 residues 30 . Importantly, these antibodies vary in their neutralization potency and breath, 58,69 however, whether they vary in their ability to provoke ADCP and if levels of ADCP correlate with antibodies that target certain epitopes remain unknown.…”

“…The HCV envelope protein E1E2 with the different domains (Dom) and/or antigenic regions (AR) targeted by specific monoclonal antibodies used for epitope mapping of plasma anti-E2 antibodies produced by patients is shown in Figure 6A for reference. 30 A statistical correlation matrix showed that antibodies in patient plasma…”