T cell recognition of hypervariable region-1 from hepatitis C virus envelope protein with multiple class II MHC molecules in mice and humans: Preferential help for induction of antibodies to the hypervariable region

Hypervariable region-1 (HVR1) from the hepatitis C virus (HCV) envelope pro tein is thought to be a target for neutralizing Abs, To explore HVR1 recogn ition by helper T cells, and their role in Ab responses, we attempted to ge nerate helper T cells specific for HVR1 in mice of three MHC types, and wit h PBMC from HCV-infected HLA-diverse humans. In both species, HVR1 was pres ented by >1 class II MHC molecule to CD4(+) helper T cells and showed surpr ising interisolate cross-reactivity, The epitope for two DR4(+) patients wa s mapped to a more conserved C-terminal sequence containing a DR4 binding m otif, possibly accounting for cross-reactivity, Strikingly, Abs to patients ' own HVR1 sequences were found only in patients with T cell responses to H VR1, even though all had Abs to envelope protein, suggesting that induction of Abs to HVR1 depends on helper T cells specific for a sequence proximal to the Ab epitope, Thus, helper T cells specific for HVR1 may be functional ly important in inducing neutralizing Abs to HCV, These results may be the first example of "T-B reciprocity," in which proximity of a helper T cell e pitope determines Ab epitope specificity, in a human disease setting.