Abstract
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.
Highlights
Neutralizing antibodies can inhibit virus infection by impeding one of several critical steps of the virus lifecycle
Our group recently generated a highly inhibitory monoclonal antibody (E16) against the envelope protein of West Nile virus, which can abort infection in animals even after the virus has spread to the brain
We show that E16 blocks infection by preventing West Nile virus from transiting from endosomes, an obligate step in the entry pathway of the viral lifecycle
Summary
Neutralizing antibodies can inhibit virus infection by impeding one of several critical steps of the virus lifecycle. These include blocking attachment to the cell surface, interaction with host factors required for internalization, and structural transitions on the virion that drive membrane fusion (reviewed in [1,2]). Antibodies can independently neutralize virus infection by promoting virus aggregation, destabilizing virion structure, and blocking budding or release from the cell surface (reviewed in [3]). Many of the most potently neutralizing antibodies inhibit infection by interfering with required interactions between viruses and obligate cellular receptors (e.g., rhinovirus and ICAM1, HIV and CD4 or CCR5, and poliovirus and CD155). There is currently no approved vaccine or therapy for WNV infection
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