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Defining of MAbs-neutralizing sites on the surface glycoproteins Gn and Gc of a hantavirus using vesicular stomatitis virus pseudotypes and site-directed mutagenesis
Univ Helsinki, Dept Virol, Med, Helsinki, Finland.
Univ Helsinki, Dept Virol, Med, Helsinki, Finland.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Univ Helsinki, Dept Virol, Med, Helsinki, Finland;Helsinki Univ Hosp, Dept Virol & Immunol, HUSLAB, Helsinki, Finland;Univ Helsinki, Dept Vet Biosci, Helsinki, Finland.
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2019 (English)In: Journal of General Virology, ISSN 0022-1317, E-ISSN 1465-2099, Vol. 100, no 2, p. 145-155Article in journal (Refereed) Published
Abstract [en]

Earlier four monoclonal antibodies (MAbs) against surface glycoproteins Gn and Gc of puumala virus (PUUV, genus Orthohantavirus, family Hantaviridae, order Bunyavirales) were generated and for three MAbs with neutralizing capacity the localization of binding epitopes was predicted using pepscan and phage-display techniques. In this work, we produced vesicular stomatitis virus (VSV) particles pseudotyped with the Gn and Gc glycoproteins of PUUV and applied site-directed mutagenesis to dissect the structure of neutralizing epitopes. Replacement of cysteine amino acid (aa) residues with alanines resulted in pseudotype particles with diminished (16 to 18 %) neut-titres; double Cys -> Ala mutants, as well as mutants with bulky aromatic and charged residues replaced with alanines, have shown even stronger reduction in neut-titres (from 25 % to the escape phenotype). In silico modelling of the neut-epitopes supported the hypothesis that these critical residues are located on the surface of viral glycoprotein molecules and thus can be recognized by the antibodies indeed. A similar pattern was observed in experiments with mutant pseudotypes and sera collected from patients suggesting that these neut-epitopes are utilized in a course of human PUUV infection. These data will help understanding the mechanisms of hantavirus neutralization and assist construction of vaccine candidates.

Place, publisher, year, edition, pages
MICROBIOLOGY SOC , 2019. Vol. 100, no 2, p. 145-155
Keywords [en]
Monoclonal antibody, neutralizing epitope, site-directed mutagenesis
National Category
Microbiology in the medical area
Identifiers
URN: urn:nbn:se:uu:diva-377671DOI: 10.1099/jgv.0.001202ISI: 000457868300005PubMedID: 30624178OAI: oai:DiVA.org:uu-377671DiVA, id: diva2:1291516
Available from: 2019-02-25 Created: 2019-02-25 Last updated: 2019-02-25Bibliographically approved

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Lundkvist, Åke

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