Abstract
Hepatitis C virus (HCV) is a major causative agent of acute and chronic hepatitis. It is estimated that 400,000 people die every year from chronic HCV infection, mostly from severe liver-related diseases such as cirrhosis and liver cancer. Although HCV was discovered more than 30 years ago, an efficient prophylactic vaccine is still missing. The HCV glycoprotein complex, E1/E2, is the principal target of neutralizing antibodies (NAbs) and, thus, is an attractive antigen for B-cell vaccine design. However, the high genetic variability of the virus necessitates the identification of conserved epitopes. Moreover, the high intrinsic mutational capacity of HCV allows the virus to continually escape broadly NAbs (bNAbs), which is likely to cause issues with vaccine-resistant variants. Several studies have assessed the barrier-to-resistance of vaccine-relevant bNAbs in vivo and in vitro. Interestingly, recent studies have suggested that escape substitutions can confer antibody resistance not only by direct modification of the epitope but indirectly through allosteric effects, which can be grouped based on the breadth of these effects on antibody susceptibility. In this review, we summarize the current understanding of HCV-specific NAbs, with a special focus on vaccine-relevant bNAbs and their targets. We highlight antibody escape studies pointing out the different methodologies and the escape mutations identified thus far. Finally, we analyze the antibody escape mechanisms of envelope protein escape substitutions and polymorphisms according to the most recent evidence in the HCV field. The accumulated knowledge in identifying bNAb epitopes as well as assessing barriers to resistance and elucidating relevant escape mechanisms may prove critical in the successful development of an HCV B-cell vaccine.
Highlights
Hepatitis C virus (HCV) infection is one of the leading causes of liver-related disease and liver transplantation in developed countries [1,2]
The receptor binding domain (RBD) contains amino acids critical for binding to the HCV co-receptor, CD81 (Figures 1 and 2A), along with conserved epitopes that are the target of neutralizing antibodies (NAbs) with broad neutralization activity and, it has been suggested that most broadly NAbs (bNAbs) inhibit HCV infection by blocking
AS434 is a linear epitope composed of highly conserved residues important for E2 binding to CD81 [71,72]; AS434 is recognized by both bNAbs and non-neutralizing antibodies [52,72]
Summary
Hepatitis C virus (HCV) infection is one of the leading causes of liver-related disease and liver transplantation in developed countries [1,2]. The RBD contains amino acids critical for binding to the HCV co-receptor, CD81 (Figures 1 and 2A), along with conserved epitopes that are the target of NAbs with broad neutralization activity (bNAbs) and, it has been suggested that most bNAbs inhibit HCV infection by blocking. Some antibodies against AS412 and AS434 have shown broad neutralization activity, and these antigenic sites have been proposed as useful targets in HCV vaccine designs [48,54]. AS434 is a linear epitope composed of highly conserved residues important for E2 binding to CD81 [71,72]; AS434 is recognized by both bNAbs and non-neutralizing antibodies [52,72]. The successful targeting of these clusters is likely to be instrumental in developing an HCV vaccine
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