Antibody responses to hepatitis C virus hypervariable region 1: Evidence for cross-reactivity and immune-mediated sequence variation

Sequence heterogeneity of hepatitis C virus (HCV) is unevenly distributed a long the genome, and maximal variation is confined to a short sequence of t he HCV second envelope glycoprotein (E2), designated hypervariable region 1 (HVR1), whose biological function is still undefined. We prospectively stu died serological responses to synthetic oligopeptides derived from HVR1 seq uences of patients with acute and chronic HCV infection obtained at baselin e and after a defined follow-up period. Extensive serological cross-reactiv ity for unrelated HVR1 peptides was observed in the majority of the patient s. Antibody response was restricted to the IgG1 isotype and was focused on the carboxyterminal end of the HVR1 region. Cross-reactive antibodies could be readily elicited following immunization of mice with multiple antigenic peptides carrying HVR1 sequences derived from our patients. The vigor and heterogeneity of cross-reactive antibody responses were significantly highe r in patients with chronic hepatitis compared with those with acute hepatit is and in patients infected with HCV type 2 compared with patients infected with other viral genotypes (predominantly type 1), which suggest that high er time-related HVR1 sequence diversification previously described for type 2 may result from immune selection. The finding of a statistically signifi cant correlation between HVR1 sequence variation, and intensity, and crossr eactivity of humoral immune responses provided stronger evidence in support of the contention that HCV variant selection is driven by the host's immun e pressure.