Hepatitis C virus plays hide and seek with neutralizing antibodies.

Hepatitis C virus (HCV) evades immune responses to establish a chronic infection. These viral evasion mechanisms pose a formidable challenge to vaccine development. In this issue of HEPATOLOGY Prentoe et al. report important observations that guide the development of vaccination strategies for induction of potent cross-neutralizing antibodies. While the importance of cellular immunity for control of HCV has been appreciated for a long time, more recent evidence also supports a vital role of neutralizing antibodies. For instance, among women accidentally infected with HCV, acutely resolving patients displayed significantly stronger neutralizing antibody responses early after infection compared to those developing a chronic course. Moreover, in mouse models neutralizing antibodies can prevent or even clear an HCV infection. These results encourage vaccination approaches aiming for induction of neutralizing antibody responses. However, the viral epitopes that should be targeted are only beginning to emerge, and strategies to elicit such antibodies are largely elusive. It is well established that the amino-terminal domain of the viral envelope protein 2 (E2) is immunogenic and induces antibodies that neutralize HCV. However, this domain is flexible and tolerates mutations. Thus, it evolves rapidly—in fact, it is the most variable portion of the HCV genome and, therefore, called hypervariable region 1 (HVR1)—and serves as a “decoy” for antibodies. Not only this but HVR1 also occludes viral protein domains that are not so flexible and are thus highly conserved. This occlusion impedes access of antibodies to these epitopes and limits neutralization. The epitopes affected by HVR1 occlusion include, for instance, the conformational binding site to the key HCV entry factor cluster of differentiation 81 (CD81). HCV attaches to the cell surface primarily by binding to glycosaminoglycans and scavenger receptor class B type 1. These initial contacts may elicit conformational changes that expose the binding site to CD81, thus facilitating interactions with CD81 and downstream entry factors (Fig. 1). Thus, highly “vulnerable,” conserved epitopes would only be fully uncovered when HCV has reached its target cell’s surface and is poised to enter. This entry mechanism would limit access of antibodies targeting conserved protein domains and therefore contribute to immune evasion and maintenance of a chronic infection. Prentoe and coauthors now add new information to our understanding of the interplay between antibodies and HVR1. They used a panel of HCV strains representing all major HCV genotypes and a set of the most powerful available cross-neutralizing monoclonal antibodies targeting a spectrum of distinct subdomains of the E1-E2 protein heterodimer (antigenic domains A-D and antigenic region 1 [AR1]-AR5; Fig. 1) and compared virus antibody binding and neutralization between the parental viruses and the respective variants lacking HVR1. Using this approach, they first convincingly show that the respective viruses lacking HVR1 are much more susceptible to neutralization by Abbreviations: AR, antigenic region; CD81, cluster of differentiation 81; E1/E2, envelope proteins 1 and 2; HCV, hepatitis C virus; HVR1, hypervariable region 1.