Hepatitis C virus (HCV) is a major cause of liver disease worldwide and there is a pressing need for the development of a preventative vaccine as well as new treatments. It was recently demonstrated that the mouse monoclonal antibody (mAb) AP33 potently neutralizes infectivity of HCV pseudoparticles (HCVpp) carrying E1E2 envelopes representative of all of the major genotypes of HCV. This study determined the prevalence of human serum antibodies reactive to the region of HCV E2 recognized by AP33. Antibodies recognizing this region were present in less than 2.5 % of sera obtained from individuals with chronic HCV infection. A similar prevalence was found in a smaller cohort of individuals who had experienced an acute infection, suggesting that AP33-like antibodies do not play a major role in natural clearance of HCV infection. Sera exhibited different patterns of reactivity to a panel of peptides representing circulating variants, highlighting the presence of distinct epitopes in this region. Only two sera contained antibodies that could recognize a specific AP33-reactive peptide mimotope. AP33-like antibodies made a measurable contribution to the ability of these sera to inhibit E2-CD81 interaction, but not to the overall neutralization of cell entry. Together, these data show that antibodies to the AP33 epitope are not commonly generated during natural infection and that generation of such antibodies via vaccination may require modified immunogens to focus the generation of specific antibodies. Importantly, individuals harbouring AP33-like antibodies are an important potential source of human mAbs for future therapeutic development.
Chronic hepatitis C virus (HCV) infection can persist even in the presence of a broadly neutralizing antibody response. Various mechanisms that underpin viral persistence have been proposed, and one of the most recently proposed mechanisms 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 to 423 can be inhibited by nonneutralizing antibodies binding to a less conserved region encompassing residues 434 to 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 HCV pseudoparticle (HCVpp) and cell culture-infectious virus (HCVcc) infection albeit with different breadths and potencies. Epitope mapping revealed the presence of overlapping but distinct epitopes in both regions, which may explain the observed differences in neutralizing phenotypes. Crucially, we failed to demonstrate any inhibition between these two groups of antibodies, suggesting that interference by nonneutralizing antibodies, at least for the region encompassing residues 434 to 446, does not provide a mechanism for HCV persistence in chronically infected individuals. H epatitis C virus (HCV) has infected approximately 180 million people worldwide (2). Following infection, most people fail to clear the virus, and a chronic infection, often with serious sequelae, ensues (1, 38). HCV-related end-stage liver disease is the leading indication for liver transplantation, and reinfection of the grafted liver occurs rapidly (32). A systematic review of the research literature recently suggested that there is little, if any, benefit gained by the treatment of liver transplant recipients with standard antiviral regimens (24), and possible adverse effects associated with newly emerging direct-acting antivirals may limit their usefulness in this clinical setting. Antibodies are usually well tolerated, and the successful administration of anti-hepatitis B virus immunoglobulin (Ig) (HBIG) (50, 59) sets an important precedent for HCV. The administration of HCV-neutralizing antibodies during the anhepatic phase and following transplantation could likewise prevent the reinfection of the grafted liver; the reduced incidence of HCV in individuals receiving HBIG containing anti-HCV antibodies (20) supports this notion. However, to date, the therapeutic administration of serum immunoglobulin or monoclonal antibodies targeting HCV has been disappointing (10, 51), indicating that further studies of the polyclonal response are needed, if we are to harness the opportunity that antibody therapy offers.There is also an urgent need for the development of safe and effective HCV vaccines to prevent infection. Significant progress has been made toward T-cell-based vaccines (22), but these vaccines will not be sufficient to elici...
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