Antibodies in Human Sera Specific to Hypervariable Region 1 of Hepatitis C Virus Can Block Viral Attachment

Abstract

It has been postulated that antibodies specific to the hypervariable region 1 (HVR1) within the putative envelop protein E2 of hepatitis C virus (HCV) can neutralize virus. We studied such antibodies in sera of patients who were infected in a single-source outbreak by a contaminated anti-D immunoglobulin preparation (HCV-AD78). The nucleotide sequences of cDNAs encoding HVR1 of HCV-AD78 were determined. The four major variants (HVR1.A, B, C, and D) were expressed as fusion proteins in Escherichia coli. Sixty-seven percent of sera contained antibodies to HVR1.A. Sera unrelated to infection of the outbreak also recognized HVR1.A but to a lesser extent (15%), suggesting that not all HVR1-specific antibodies are absolutely isolate-specific. Antibodies directed against individual variants of HVR1 were found in sera obtained early postinfection (p.i.) (< or = 1 year) but also in sera obtained several years later. An in vitro binding assay of HCV to tissue culture cells was employed to further characterize these sera. Five of seven sera that were obtained early p.i. prevented binding of HCV to cells. Preincubation of such sera with HVR1-specific fusion proteins restored binding of HCV to cells in four of five sera. These findings suggest that the majority of neutralizing antibodies are directed against HVR1.

Evidence for cross-genotype neutralization of hepatitis C virus pseudo-particles and enhancement of infectivity by apolipoprotein C1

“…However, it has also been shown that a humoral immune response against HCV envelope glycoproteins, in particular against the HVR1, correlated with the clearance of this virus (3,4). It is often not possible to obtain sufficiently early and frequent samples from humans to study the temporal course of viremia, cell-mediated immune responses, and antibody responses and, therefore, experimentally infected chimpanzees offer a significant advantage for studying HCV.…”

“…The role of the humoral immune response is less well defined. Nevertheless, it has been shown that an antibody response against the envelope proteins, in particular the hypervariable region 1 (HVR1) of E2, correlated with viral clearance (3,4). In vitro and in vivo studies demonstrated that certain antibodies neutralized HCV and͞or blocked attachment of HCV to target cells and prevented infection (reviewed in ref.…”

Quasispecies of hepatitis C virus in serum and in three different parts of the liver of patients with chronic hepatitis

“…The quasispecies nature of HCV seemed to relate to the pathogenesis of persistent infection 8,9,22,23 and to the effectiveness of interferon therapy, 5,10,11 but its pathogenetic significance is still unknown. Although, hepatocytes are thought to be the principal site of HCV replication, there have only been a few studies on the quasispecies nature of liver [12][13][14]24 and the results of these studies were conflicting.…”

Monoclonal Antibodies with Broad Specificity for Hepatitis C Virus Hypervariable Region 1 Variants Can Recognize Viral Particles

“…Several lines of experimental evidence argue in favor of a dominant role of positive selection for amino acid changes in driving the pattern of HVR1 genetic diversification (1,2). Prospective studies of serological responses to synthetic oligopeptides derived from HVR1 sequences of patients with acute and chronic HCV infection showed apparently extensive serological cross-reactivity for unrelated HVR1 peptides in the majority of the patients (3)(4)(5)(6)(7)(8)(9). A significant correlation was found between HVR1 sequence variation and the intensity and cross-reactivity of humoral immune responses, strongly supporting the contention that HCV variant selection is driven by the host immune response (9).…”