Nonneutralizing human antibody fragments against hepatitis C virus E2 glycoprotein modulate neutralization of binding activity of human recombinant Fabs

Evidence from clinical and experimental studies indicates that hepatitis C virus E2 (HCV/E2) glycoprotein is the major target of a putatively protecti ve immune response. However, even in the presence of a vigorous production of anti-HCV/E2 antibodies, reinfection can occur. Dissection of the human i mmune response against HCV/E2 indicated that blocking of binding of HCV/E2 to target cells [neutralization of binding (NOB) activity] varies widely am ong antibody clones. Moreover, in vivo, simultaneous binding of antibodies to distinct epitopes can induce conformational changes and synergies that m ay be relevant to understanding the anti-HCV immune response. In this study , human recombinant Fabs were generated by affinity-selecting a phage displ ay repertoire library with antibody-coated HCV/E2. These Fabs, which share the same complementarity-determining region DNA sequences, had higher affin ity than other anti-HCV/E2 Fabs but showed no NOB activity even at the high est concentrations, Binding of Fabs to HCV/E2 caused conformational changes modifying Fab-binding patterns and reducing, with a negative synergistic e ffect, Fab-mediated NOB activity. These data suggest that some antibody clo nes have the potential to modify HCV/E2 conformation and that in this state , binding of this glycoprotein to its cellular target is less prone to inhi bition by some antibody clones. This can explain why high anti-HCV/E2 antib ody titers do not directly correlate with protection from infection. Inform ation on the interactions among different antibody clones can contribute to understanding virus-host interplay and developing more effective vaccines. (C) 2001 Academic Press.