Sequence heterogeneity of hepatitis C virus (HCV) is unevenly distributed along the genome, and maximal variation is confined to a short sequence of the HCV second envelope glycoprotein (E2), designated hypervariable region 1 (HVR1), whose biological function is still undefined. We prospectively studied serological responses to synthetic oligopeptides derived from HVR1 sequences of patients with acute and chronic HCV infection obtained at baseline and after a defined follow-up period. Extensive serological cross-reactivity for unrelated HVR1 peptides was observed in the majority of the patients. 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 higher in patients with chronic hepatitis compared with those with acute hepatitis and in patients infected with HCV type 2 compared with patients infected with other viral genotypes (predominantly type 1), which suggest that higher time-related HVR1 sequence diversification previously described for type 2 may result from immune selection. The finding of a statistically significant correlation between HVR1 sequence variation, and intensity, and crossreactivity of humoral immune responses provided stronger evidence in support of the contention that HCV variant selection is driven by the host's immune pressure. (HEPATOL-OGY 1999;30:537-545.)Hepatitis C virus (HCV) causes chronic infection in more than 60% of exposed individuals through pathogenetic mechanisms that are still poorly understood. 1 Similarly to human immunodeficiency virus (HIV), HCV is able to persist for a virtually indefinite period of time in the host, despite the coexistence of virus-specific immune responses. 2 How HCV induces chronic infection in the face of detectable cellular and humoral immune responses is currently unknown, but the ability of the virus to undergo rapid and substantial sequence modifications is thought to be a major factor in this process. [2][3][4][5][6][7][8][9][10][11] Sequence variation is unevenly distributed along the HCV genome with maximal nucleotide and aminoacid replacements being localized in a stretch of 31 residues at the N-terminus of the second envelope glycoprotein (E2) region named hypervariable region 1 (HVR1). 12 Sequential studies of sequence changes in acute and chronic HCV infection have shown that viral variants are continuously being selected in this region 13,14 and, therefore, HVR1 variation may be a mechanism by which HCV evades neutralizing responses, leading to persistent infection.Most studies point to HVR1 as the major immunogenic domain of E2, although the presence of additional B-cell sites outside HVR1 has been documented, 15 and a conserved B-cell epitope, only partially overlapping with HVR1, has been recently described that competes for ...
The hypervariable region 1 (HVR1) of the E2 protein of hepatitis C virus (HCV) is a highly heterogeneous sequence that is promiscuously recognized by human sera via binding to amino acid residues with conserved physicochemical properties. We generated a panel of mAbs from mice immunized with HVR1 surrogate peptides (mimotopes) affinity-selected with sera from HCV-infected patients from a phage display library. A high number of specific clones was obtained after immunization with a pool of nine mimotopes, and the resulting mAbs were shown to recognize several 16- and 27-mer peptides derived from natural HVR1 sequences isolated from patients with acute and chronic HCV infection, suggesting that HVR1 mimotopes were efficient antigenic and immunogenic mimics of naturally occurring HCV variants. Moreover, most mAbs were shown to bind HVR1 in the context of a complete soluble form of the E2 glycoprotein, indicating recognition of correctly folded HVR1. In addition, a highly promiscuous mAb was able to specifically capture bona fide viral particles (circulating HCV RNA) as well as rHCV-like particles assembled in insect cells expressing structural viral polypeptides derived from an HCV 1a isolate. These findings demonstrate that it is possible to induce a broadly cross-reactive clonal Ab response to multiple HCV variants. In consideration of the potentially important role of HVR1 in virus binding to cellular receptor(s), such a mechanism could be exploited for induction of neutralizing Abs specific for a large repertoire of viral variants.
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