A combination of two resistance mechanisms is critical for tick-borne encephalitis virus escape from a broadly neutralizing human antibody
Pavel Svoboda,
Jan Haviernik,
Petr Bednar,
Milos Matkovic,
Tomás Cervantes Rincón,
Jennifer Keeffe,
Martin Palus,
Jiri Salat,
Marianna Agudelo,
Michel C. Nussenzweig,
Andrea Cavalli,
Davide F. Robbiani,
Daniel Ruzek
Affiliations
Pavel Svoboda
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
Jan Haviernik
Veterinary Research Institute, Brno, Czech Republic; Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
Petr Bednar
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
Milos Matkovic
Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland
Tomás Cervantes Rincón
Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland
Jennifer Keeffe
California Institute of Technology, Pasadena, CA, USA
Martin Palus
Veterinary Research Institute, Brno, Czech Republic; Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, Ceske Budejovice, Czech Republic
Jiri Salat
Veterinary Research Institute, Brno, Czech Republic; Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, Ceske Budejovice, Czech Republic
Marianna Agudelo
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY, USA
Michel C. Nussenzweig
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY, USA; Howard Hughes Medical Institute, New York, NY, USA
Andrea Cavalli
Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland
Davide F. Robbiani
Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland; Corresponding author
Daniel Ruzek
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; Corresponding author
Summary: 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.
