|Budget Amount *help
¥2,300,000 (Direct Cost : ¥2,300,000)
Fiscal Year 1997 : ¥700,000 (Direct Cost : ¥700,000)
Fiscal Year 1996 : ¥1,600,000 (Direct Cost : ¥1,600,000)
Hypervariable region-1 (HVR1) from the hepatitis C virus (HCV) envelope protein is thought to be a target for neutralizing antibodies. To explore HVR1 recogntion by helper T cells, and their role in antibody responses, we attempted to generate helper T cells specific for HVR1 in mice of three MHC types, and with PBMC from HCV-infected HLA-diverse humans. In both species, HVR1 was presented by >1 class II MHC molecule to CD4^+ helper T cells and showed surprising interisolate crossreactivity. The epitope for two DR4^+ patients was mapped to a more conserved C-terminal sequence containing a DR4 binding motif, possibly accounting for crossreactivity. Strikingly, antibodies to patients' own HVR1 sequences were found only in patients with T cell responses to HVR1, even though all had antibodies to envelope protein, suggesting that induction of antibodies to HVR1 depends on helper T cells specific for a sequence proximal to the antibody epitope. Thus, helper T cells specific for HVR1 may be functionally important in inducing neutralizing antibodies to HCV.These results may be the first example of "T-B reciprocity, " in which proximity of a helper T cell epitope determines antibody epitope specificity, in a human disease setting.