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

Warning

This publication doesn't include Faculty of Medicine. It includes Faculty of Science. Official publication website can be found on muni.cz.
Authors

SVOBODA Pavel HAVIERNIK Jan BEDNÁŘ Petr MATKOVIC Milos RINCO Tomas Cervantes KEEFFE Jennifer PALUS Martin SALAT Jiri AGUDELO Marianna NUSSENZWEIG Michel C CAVALLI Andrea ROBBIANI Davide F RŮŽEK Daniel

Year of publication 2023
Type Article in Periodical
Magazine / Source Cell Reports
MU Faculty or unit

Faculty of Science

Citation
Web https://doi.org/10.1016/j.celrep.2023.113149
Doi http://dx.doi.org/10.1016/j.celrep.2023.113149
Keywords tick-borne encephalitis; tick-borne encephalitis virus; monoclonal antibody; escape mutant; neutralization
Description 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.
Related projects:

You are running an old browser version. We recommend updating your browser to its latest version.

More info