Humoral immune response to hypervariable region 1 of the putative envelope glycoprotein (gp70) of hepatitis C virus

Abstract

We recently found that alterations of amino acids in hypervariable region 1 (HVR1) of the putative envelope glycoprotein (gp70) of hepatitis C virus (HCV) occurred sequentially in the chronic phase of hepatitis at intervals of several months. This finding suggests that mutations in HVR1 are involved in the mechanism of persistent chronic HCV infection involving escape from the immunosurveillance system. To explore this possibility, we examined the humoral immune response to HVR1 with our assay system, in which immunoprecipitation was carried out with sera from patients by using an HVR1 (27-amino-acid) dihydrofolate reductase fusion protein synthesized by in vitro transcription and translation. Results showed that HVR1 contains a sequence-specific immunological epitope that induces the production of antibodies restricted to the specific viral isolate. Furthermore, analysis of the kinetics of the appearance of antibodies in two patients with chronic hepatitis, with whom successive alterations of amino acids of HVR1 have been observed, showed that the titers of anti-HVR1 antibodies usually reached maximal levels several months after the isolation of HCV having the specific sequence of HVR1. This observation suggests that anti-HVR1 antibodies are involved in the genetic drift of HVR1 (minor antigenic variation) by immunoselection. However, the coexistence of HVR1 as an antigen and its specific antibody was sometimes observed. The possibility that HVR1 acts as a neutralizing epitope is discussed.

Occurrence of identical hypervariable region 1 sequences of hepatitis C virus in transfusion recipients and their respective blood donors: Divergence over time

“…Thus, the more rapid evolution of HVR1 in the acute hepatitis period could reflect the presence of neutralizing antibodies directed at the viral envelope. Indeed, epitopes are present in some HVR1 sequences that induce the formation of humoral antibodies, 26,[28][29][30][31] and neutralizing activity has been shown with antibodies directed against particular HVR1 sequences. 7,27,32,33 The observed evolution of HVR1 also could be caused by the activity of HCV-specific CTLs.…”

Hepatitis C Virus Resistance to Antiviral Therapy

“…HVR1 contains one of the principal HCV-neutralizing epitopes and also appears to be a target for cytotoxic responses. [110][111][112][113] We showed that IFN-␣ administration and subsequent withdrawal result in shifts of HVR1 nucleotide sequences in more than 70% of patients infected with the most frequent HCV genotypes (i.e., 1a, 1b, 2a, 2c, 3a, and 4a) receiving IFN-␣ in monotherapy. 79 Similar changes are observed in patients receiving the combination of IFN-␣ and ribavirin.…”

Mimotopes of the hepatitis C virus hypervariable region 1, but not the natural sequences, induce cross-reactive antibody response by genetic immunization

“…However, antibodies against a single E2 HVR1 are isolate-specific, 24 and lead to the emergence of escape mutants during chronic infection. [16][17][18][19][20][21] Because of the large inter-and intra-individual heterogeneity of this viral region, a major task in developing an HCV vaccine would be to generate an immunogen that induces highly cross-reactive anti-HVR1 response to prevent outgrowth of escape mutants, rather than require the immune system to deal with them after they arise. In this work, we have tested several plasmids encoding HCV E2 to evaluate their potential of inducing a cross-reacting anti-HVR1 response.…”

“…10 In fact, HCV displays a high rate of mutation during replication and exists in the bloodstream of infected patients as a quasispecies, [11][12][13][14][15] which fluctuates during the course of the disease mainly as a result of immune pressure. [15][16][17][18][19][20][21][22][23] The major target of this immune response is the 27 amino acid-long N-terminal segment of the E2 glycoprotein. This protein fragment is the most variable region of the whole HCV polyprotein 11 and contains a principal neutralization determinant, 24 but anti-hypervariable region 1 (HVR1) antibodies specific for one variant display only a limited ability to block different viral variants.…”