A therapeutic antibody against west nile virus neutralizes infection by blocking fusion within endosomes

• Published in: PLoS pathogens Vol. 5; no. 5; p. e1000453
• Main Authors: Thompson, Bruce S, Moesker, Bastiaan, Smit, Jolanda M, Wilschut, Jan, Diamond, Michael S, Fremont, Daved H
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.05.2009; Public Library of Science (PLoS)
• Subjects: Antibodies, Monoclonal; Antibodies, Viral - pharmacology; Antibodies, Viral - therapeutic use; Binding sites; Care and treatment; Causes of; Development and progression; Encephalitis; Endosomes - virology; Experiments; Health aspects; Immunology/Immune Response; Immunology/Immunity to Infections; Infectious Diseases/Viral Infections; Lysosomes - virology; Microbiology; Microbiology/Immunity to Infections; Microscopy; Monoclonal antibodies; Physiological aspects; Proteins; Viral Envelope Proteins - immunology; Viral infections; Virus Internalization; Viruses; West Nile fever; West Nile Fever - immunology; West Nile virus; West Nile virus - immunology; United States; Netherlands
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1000453

Defining the precise cellular mechanisms of neutralization by potently inhibitory antibodies is important for understanding how the immune system successfully limits viral infections. We recently described a potently inhibitory monoclonal antibody (MAb E16) against the envelope (E) protein of West Nile virus (WNV) that neutralizes infection even after virus has spread to the central nervous system. Herein, we define its mechanism of inhibition. E16 blocks infection primarily at a post-attachment step as antibody-opsonized WNV enters permissive cells but cannot escape from endocytic compartments. These cellular experiments suggest that E16 blocks the acid-catalyzed fusion step that is required for nucleocapsid entry into the cytoplasm. Indeed, E16 directly inhibits fusion of WNV with liposomes. Additionally, low-pH exposure of E16-WNV complexes in the absence of target membranes did not fully inactivate infectious virus, further suggesting that E16 prevents a structural transition required for fusion. Thus, a strongly neutralizing anti-WNV MAb with therapeutic potential is potently inhibitory because it blocks viral fusion and thereby promotes clearance by delivering virus to the lysosome for destruction.