Serological responses to HCV hypervariable region 1 are mainly cross-reactive and genotype-dependent.

HCV circulates as a quasispecies of highly related molecular variants which are probably continuously selected by the host's immune pressure. To test this h)1~othesis, hypervariable region 1 (HVR1) sequences from 12 patients with chronic HCV infection were PCR amplified from sera collected at enttry (tO) and after 12 months (t12). Biotinilated 16-mer peptides were then synthesised on the basis of the predominant HVR1 deduced amino acid sequences isolated at tO and t12 and used in ELISA using streptavidin-coated plates. Strong serological reactivities were generally noted for peptides derived from the patients' own HVR1 sequences and, unexpectedly, also for several peptides derived from unrelated and highly divergent variants. Binding of sera to different peptides was independent of titer and could only be partially inhibited by prior absorption with streptavidin-coated magnetic beads saturated with cross-reactive peptides. To exclude the possibility of an artifact, we tested serological reactivities of 46 additional chronically-infected patients and found that virtually all had circulating antibodies that bound to unrelated HVR1 peptides, indicating significant cross-reactivity in this region. In contrast, only 2 out of 6 patients with acute hepatitis C showed limited HVR1 peptide reactivity, suggesting that cross-reactive B-cell responses develop mainly during persistent infection. We next analysed serological responses to HVR1 with respect to HCV type and ALT values and found that such responses were significantly more intense and more broadly reactive in type 2-infected subjects compared with subjects infected by other types (lntensity p<0.04, heterogeneity p<0.02, entropy p<0.02). In conclusion, the stronger immune pressure on HVR1 observed in subjects infected with HCV type 2 may result in a more efficient control of chronic liver disease and may be responsible for the reportedly higher mutation rate in this region in type 2 compared with type l-infected subjects.