B Cell Responses and Control of HCV Infection

Abstract

Humoral immunity is the primary correlate of protection for most preventive vaccines. For hepatitis C virus (HCV), early animal studies provided support for the importance of virus neutralizing antibodies to facilitate clearance of infection. The development of retroviral pseudotype particles expressing HCV E1E2 glycoproteins (HCVpp), infectious cell culture-derived HCV virions (HCVcc), and small animal models of acute HCV infection have made possible the measurement of in vitro and in vivo antibody-mediated virus neutralization. Their applications in multiple studies clearly established the importance of neutralizing antibodies in controlling HCV infection. However, the virus has devised a number of decoys of highly immunogenic regions associated with viral escape or non-neutralizing antibodies that deflect the immune response from less immunogenic conserved regions mediating virus neutralization that are not associated with viral escape or escape with compromised fitness. The focus of this review is on the immunogenic determinants on E2, which are roughly segregated into the hypervariable region 1 (HVR1), and five clusters of overlapping epitopes, designated as antigenic domains A-E. A detailed understanding of conserved neutralizing epitopes within these antigenic domains that are not associated with escape and how other antigenic regions or decoys serve as diversions of the immune response and/or elicit antibodies that negatively modulate broadly neutralizing antibodies will provide a roadmap in rational design for an HCV vaccine.