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

0579676 - BC 2024 RIV US eng J - Článek v odborném periodiku
Svoboda, Pavel - Haviernik, J. - Bednář, P. - Matkovic, M. - Rincon, T. C. - Keeffe, J.R. - Palus, Martin - Salát, Jiří - Agudelo, M. - Nussenzweig, M.C. - Cavalli, A. - Robbiani, D.F. - Růžek, Daniel
A combination of two resistance mechanisms is critical for tick-borne encephalitis virus escape from a broadly neutralizing human antibody.
Cell Reports. Roč. 42, č. 9 (2023), č. článku 113149. ISSN 2211-1247. E-ISSN 2211-1247
Grant CEP: GA ČR(CZ) GF21-05445L; GA MŠMT(CZ) LX22NPO5103
Institucionální podpora: RVO:60077344
Klíčová slova: envelope protein * monoclonal-antibodies * amino-acid * neuroinvasiveness * mutants * identification * glycoprotein * mutations * variants * epitope
Obor OECD: Virology
Impakt faktor: 8.8, rok: 2022
Způsob publikování: Open access
https://www.sciencedirect.com/science/article/pii/S2211124723011610?via%3Dihub

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.
Trvalý link: https://hdl.handle.net/11104/0348490