Date Published: March 21, 2019
Publisher: Public Library of Science
Author(s): Jagdish Suresh Patel, Caleb J. Quates, Erin L. Johnson, F. Marty Ytreberg, Jens H. Kuhn.
The 2014 outbreak of Ebola virus disease (EVD) in Western Africa is the largest recorded filovirus disease outbreak and led to the death of over 11,000 people. The recent EVD outbreaks (since May 2018) in the Democratic Republic of the Congo has already claimed the lives of over 250 people. Tackling Ebola virus (EBOV) outbreaks remains a challenge. Over the years, significant efforts have been put into developing vaccines or antibody therapies which rely on an envelope glycoprotein (GP) of Zaire ebolavirus (strain Mayinga-76). Therefore, one key approach for combating EVD epidemics is to predict mutations that may diminish the effectiveness of the treatment. In a previous study we generated a watch list of potential antibody escape mutations of EBOV GP against the monoclonal antibody KZ52. Molecular modeling methods were applied to the three-dimensional experimental structure of EBOV GP bound to KZ52 to predict the effect of every possible single mutation in EBOV GP. The final watch list contained 34 mutations that were predicted to destabilize binding of KZ52 to EBOV GP but did not affect EBOV GP folding and its ability to form trimers. In this study, we expand our watch list by including three more monoclonal antibodies with distinct epitopes on GP, namely Antibody 100 (Ab100), Antibody 114 (Ab114) and 13F6-1-2. Our updated watch list contains 127 mutations, three of which have been seen in humans or are experimentally associated with reduced efficacy of antibody treatment. We believe mutations on this watch list require attention since they provide information about circumstances in which interventions could lose the effectiveness.
Ebolavirus has six known species: Zaire ebolavirus, Sudan ebolavirus, Taï Forest ebolavirus, Bundibugyo ebolavirus, Reston ebolavirus and Bombali ebolavirus. [1, 2] Ebola virus (EBOV) is deadly and can led to death in up to 90% cases. The Ebola virus disease (EVD) outbreak in Western Africa between 2014 to 2016 is the largest recorded filovirus disease outbreak and led to death over 11,000 people. This outbreak receded in 2016, but there are two recent EVD outbreak in the Democratic Republic of the Congo that began in May and August 2018 which have already claimed lives of 271 people and more than 458 positive cases (WHO report, 4th December 2018).
For a mutation to be placed on a watch list for EBOV it must: (1) disrupt binding to a protective antibody, and (2) leave the viral proteins functional thus allowing them to fold and assemble. It is thus necessary to determine how amino acid mutations alter stabilities (ΔΔG values) for GP folding, forming a trimer and binding to the antibody. In our previous work, we have obtained ΔΔG values of GP folding, GP trimer formation and GP binding to KZ52 antibody using our molecular dynamics (MD) plus FoldX approach. In this study we calculate ΔΔG values of binding for Ab100, Ab114 and 13F6-1-2 antigen-antibody complexes using the same modeling approach.
We have expanded the watch list generated by us in a previous study by including antibody escape mutations against three additional antibodies interacting with EBOV GP. These watch list mutations are those predicted to both disrupt GP—antibody binding and yet allow GP to fold and form trimers.