Date Published: August 23, 2018
Publisher: Public Library of Science
Author(s): Philipp A. Ilinykh, Rodrigo I. Santos, Bronwyn M. Gunn, Natalia A. Kuzmina, Xiaoli Shen, Kai Huang, Pavlo Gilchuk, Andrew I. Flyak, Patrick Younan, Galit Alter, James E. Crowe, Alexander Bukreyev, Jens H. Kuhn.
Recent studies suggest that some monoclonal antibodies (mAbs) specific for ebolavirus glycoprotein (GP) can protect experimental animals against infections. Most mAbs isolated from ebolavirus survivors appeared to target the glycan cap or the stalk region of the viral GP, which is the envelope protein and the only antigen inducing virus-neutralizing antibody response. Some of the mAbs were demonstrated to be protective in vivo. Here, a panel of mAbs from four individual survivors of ebolavirus infection that target the glycan cap or stem region were selected for investigation of the mechanisms of their antiviral effect. Comparative characterization of the inhibiting effects on multiple steps of viral replication was performed, including attachment, post-attachment, entry, binding at low pH, post-cleavage neutralization of virions, viral trafficking to endosomes, cell-to-cell transmission, viral egress, and inhibition when added early at various time points post-infection. In addition, Fc-domain related properties were characterized, including activation and degranulation of NK cells, antibody-dependent cellular phagocytosis and glycan content. The two groups of mAbs (glycan cap versus stem) demonstrated very different profiles of activities suggesting usage of mAbs with different epitope specificity could coordinate inhibition of multiple steps of filovirus infection through Fab- and Fc-mediated mechanisms, and provide a reliable therapeutic approach.
Filoviruses are enveloped, filamentous-like viruses with non-segmented RNA genome of negative polarity. The Ebolavirus genus of the Filoviridae family includes five species: Ebola (EBOV), Sudan (SUDV), Bundibugyo (BDBV), Taï Forest (TAFV) and Reston (RESTV) viruses. Most of these viruses are responsible for highly lethal disease outbreaks, for example the occurrence of 11,323 human fatalities during the 2013–2016 EBOV epidemic in West Africa [1, 2]. Despite intense international collaborative efforts, there is still no licensed therapeutic available against filovirus disease.
The unprecedented epidemic of EBOV in West Africa in 2013–2016 demonstrated the urgent need for treatments against this and related highly pathogenic filoviruses. Antibody-based therapy remains the only available effective strategy against the infection. Further progress in development of more broad and effective filovirus mAbs requires identification of the mechanism of the protective effect of these mAbs.