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A combination of two resistance mechanisms is critical for tick-borne encephalitis virus escape from a broadly neutralizing human antibody

P. Svoboda, J. Haviernik, P. Bednar, M. Matkovic, T. Cervantes Rincón, J. Keeffe, M. Palus, J. Salat, M. Agudelo, MC. Nussenzweig, A. Cavalli, DF. Robbiani, D. Ruzek

. 2023 ; 42 (9) : 113149. [pub] 20230919

Language English Country United States

Document type Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural

Persistent link   https://www.medvik.cz/link/bmc24001221

Grant support
P01 AI138938 NIAID NIH HHS - United States
U01 AI151698 NIAID NIH HHS - United States
U19 AI111825 NIAID NIH HHS - United States

Tick-borne encephalitis virus (TBEV) is a flavivirus that causes human neuroinfections and represents a growing health problem. The human monoclonal antibody T025 targets envelope protein domain III (EDIII) of TBEV and related tick-borne flaviviruses, potently neutralizing TBEV in vitro and in preclinical models, representing a promising candidate for clinical development. We demonstrate that TBEV escape in the presence of T025 or T028 (another EDIII-targeting human monoclonal antibody) results in virus variants of reduced pathogenicity, characterized by distinct sets of amino acid changes in EDII and EDIII that are jointly needed to confer resistance. EDIII substitution K311N impairs formation of a salt bridge critical for T025-epitope interaction. EDII substitution E230K is not on the T025 epitope but likely induces quaternary rearrangements of the virus surface because of repulsion of positively charged residues on the adjacent EDI. A combination of T025 and T028 prevents virus escape and improves neutralization.

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$a Svoboda, Pavel $u Veterinary Research Institute, Brno, Czech Republic; Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, Ceske Budejovice, Czech Republic; Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic; Department of Pharmacology and Pharmacy, Faculty of Veterinary Medicine, University of Veterinary Sciences, Brno, Czech Republic
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$a Tick-borne encephalitis virus (TBEV) is a flavivirus that causes human neuroinfections and represents a growing health problem. The human monoclonal antibody T025 targets envelope protein domain III (EDIII) of TBEV and related tick-borne flaviviruses, potently neutralizing TBEV in vitro and in preclinical models, representing a promising candidate for clinical development. We demonstrate that TBEV escape in the presence of T025 or T028 (another EDIII-targeting human monoclonal antibody) results in virus variants of reduced pathogenicity, characterized by distinct sets of amino acid changes in EDII and EDIII that are jointly needed to confer resistance. EDIII substitution K311N impairs formation of a salt bridge critical for T025-epitope interaction. EDII substitution E230K is not on the T025 epitope but likely induces quaternary rearrangements of the virus surface because of repulsion of positively charged residues on the adjacent EDI. A combination of T025 and T028 prevents virus escape and improves neutralization.
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$a Haviernik, Jan $u Veterinary Research Institute, Brno, Czech Republic; Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
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$a Bednar, Petr $u Veterinary Research Institute, Brno, Czech Republic; Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic; Faculty of Science, University of South Bohemia, Ceske Budejovice, Czech Republic
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$a Matkovic, Milos $u Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland
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$a Cervantes Rincón, Tomás $u Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland
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$a Keeffe, Jennifer $u California Institute of Technology, Pasadena, CA, USA
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$a Palus, Martin $u Veterinary Research Institute, Brno, Czech Republic; Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, Ceske Budejovice, Czech Republic
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$a Salat, Jiri $u Veterinary Research Institute, Brno, Czech Republic; Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, Ceske Budejovice, Czech Republic
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$a Agudelo, Marianna $u Laboratory of Molecular Immunology, The Rockefeller University, New York, NY, USA
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$a Nussenzweig, Michel C $u Laboratory of Molecular Immunology, The Rockefeller University, New York, NY, USA; Howard Hughes Medical Institute, New York, NY, USA
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$a Cavalli, Andrea $u Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland
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$a Robbiani, Davide F $u Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland. Electronic address: drobbiani@irb.usi.ch
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$a Růžek, Daniel, $d 1981- $u Veterinary Research Institute, Brno, Czech Republic; Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, Ceske Budejovice, Czech Republic; Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic; Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi City, Japan. Electronic address: ruzekd@paru.cas.cz $7 stk2008441707
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