Mimotopes of the hepatitis C virus hypervariable region 1, but not the natural sequences, induce cross-reactive antibody response by genetic immunization.
The hypervariable region 1 (HVR1) of the putative envelope protein E2 of hepatitis C virus (HCV) contains a principal neutralization epitope, and anti-HVR1 antibodies have been shown to possess protective activity in ex vivo neutralization experiments. However, the high rate of variability of this antigenic fragment may play a major role in the mechanism of escape from host immune response and might represent a major obstacle to developing an HCV vaccine. Thus, even if direct experimental evidence of the neutralizing potential of anti-HVR1 antibodies by active immunization is still missing, the generation of a vaccine candidate with a cross-reactive potential would be highly desirable. To overcome the problem of HVR1 variability, we have engineered cross-reactive HVR1 peptide mimics (mimotopes) at the N terminus of the E2 ectodomain in plasmid vectors suitable for genetic immunization. High levels of secreted and biologically active mimotope/E2 chimeras were obtained by transient transfection of these plasmids in cultured cells. All plasmids elicited anti-HVR1 antibodies in mice and rabbits with some of them leading to a cross-reacting response against many HVR1 variants from natural isolates. Epitope mapping revealed a pattern of reactivity similar to that induced by HCV infection. In contrast, plasmids encoding naturally occurring HVR1 sequences displayed either on full-length E2 in the context of the whole HCV structural region, or on a soluble, secreted E2 ectodomain, did not induce a cross-reacting anti-HVR1 response.
Istituto di Ricerche di Biologia Molecolare P. Angeletti, Pomezia, Rome, Italy; and CNRS-UMR8526, IBL/Institute Pasteur De Lille, Lille, France.
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Zucchelli
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Roccasecca
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A
Meola
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BB
Ercole
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Tafi
J
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Dubuisson
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Galfré
R
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Cortese
A
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Nicosia
D000595:Amino Acid Sequence / Q000235:genetics; D000914:Antibodies, Viral / Q000276:immunology*; D000917:Antibody Formation; D002460:Cell Line; D003429:Cross Reactions; D004279:DNA, Viral / Q000276:immunology; D000939:Epitopes; D005821:Genetic Techniques; D016174:Hepacivirus / Q000276:immunology*; D006801:Humans; D007114:Immunization / Q000379:methods*; D007135:Immunoglobulin Variable Region / Q000235:genetics* / Q000276:immunology; D007273:Injections, Intramuscular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D010957:Plasmids / Q000276:immunology; D011994:Recombinant Proteins / Q000276:immunology
D000914:Antibodies, Viral; D004279:DNA, Viral; D000939:Epitopes; D007135:Immunoglobulin Variable Region; D011994:Recombinant Proteins