A new publication in Cell Reports
Thanks to a great collaboration with colleagues from the Institute for Research in Biomedicine in Switzerland, The Rockefeller University and Caltech in the USA we are happy to reveal a combination of two resistance mechanisms which are critical for tick-borne encephalitis virus escape from a broadly neutralizing human antibody.
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.
Congratulations to Pavel Svoboda on his main first-author paper for PhD defence! :-)
Find out more here. Do you want to know the whole story? Start with our previous paper describing the characterization of highly potent neutralizing human antibodies against TBEV!
