Mechanism of Human Antibody-Mediated Neutralization of Marburg Virus

• Published in: Cell Vol. 160; no. 5; pp. 893 - 903
• Main Authors: Flyak, Andrew I., Ilinykh, Philipp A., Murin, Charles D., Garron, Tania, Shen, Xiaoli, Fusco, Marnie L., Hashiguchi, Takao, Bornholdt, Zachary A., Slaughter, James C., Sapparapu, Gopal, Klages, Curtis, Ksiazek, Thomas G., Ward, Andrew B., Saphire, Erica Ollmann, Bukreyev, Alexander, Crowe, James E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.02.2015
• Subjects: Adult; Animals; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - metabolism; Antibodies, Neutralizing - chemistry; Antibodies, Neutralizing - immunology; Antibodies, Neutralizing - isolation & purification; Antibodies, Neutralizing - metabolism; Antibodies, Viral - chemistry; Antibodies, Viral - immunology; Antibodies, Viral - metabolism; Antigen-Antibody Complex - ultrastructure; B-Lymphocytes - immunology; Female; Humans; Immunoglobulin Fab Fragments - chemistry; Immunoglobulin Fab Fragments - metabolism; Marburg Virus Disease - immunology; Marburgvirus - chemistry; Marburgvirus - genetics; Marburgvirus - immunology; Models, Molecular; Mutation; Protein Structure, Tertiary; Viral Envelope Proteins - chemistry; Viral Envelope Proteins - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2015.01.031

The mechanisms by which neutralizing antibodies inhibit Marburg virus (MARV) are not known. We isolated a panel of neutralizing antibodies from a human MARV survivor that bind to MARV glycoprotein (GP) and compete for binding to a single major antigenic site. Remarkably, several of the antibodies also bind to Ebola virus (EBOV) GP. Single-particle EM structures of antibody-GP complexes reveal that all of the neutralizing antibodies bind to MARV GP at or near the predicted region of the receptor-binding site. The presence of the glycan cap or mucin-like domain blocks binding of neutralizing antibodies to EBOV GP, but not to MARV GP. The data suggest that MARV-neutralizing antibodies inhibit virus by binding to infectious virions at the exposed MARV receptor-binding site, revealing a mechanism of filovirus inhibition. [Display omitted] •Marburg virus survivor-neutralizing antibodies bind to a single antigenic site•Several of the survivors’ antibodies also bind to Ebola virus glycoprotein•All antibodies identified bind at the predicted region of the receptor-binding site•Binding to receptor-binding site is a new mechanism of filovirus inhibition The characterization of Marburg-specific antibodies in several patients who survived the infection reveals a common binding site in the viral glycoprotein and a mechanism for filovirus inhibition.