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Laboratori di Ricerca-Area
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Infettivologica and
Biotecnologie e Tecnologie Biomediche,
Dipartimento di Malattie Infettive, and
Servizio di Virologia, IRCCS Policlinico San Matteo and University of Pavia, Pavia, Italy;
¶ Istituto di Ricerche di Biologia Molecolare "P. Angeletti," Pomezia, Italy; and
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Liver Diseases Section, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892
"Modelli per lo sviluppo di vaccini contro il virus dell’epatite C ed il micobatterio della tubercolosi," and Progetto di Ricerca Corrente 3180/98. Grant support was also provided by Schering-Plough (Italy), Fondazione Oretta Bartolomei Corsi (Firenze, Italy), and Ministero dell’Università e della Ricerca Scientifica e Technologica-Cofin no. MM06261448_003.
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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