Researchers have discovered the mechanism by which C10, a human antibody previously identified to react with the Dengue virus, prevents Zika infection at a cellular level.
To infect a cell, virus particles usually undergo two main steps, docking and fusion, which are also common targets for disruption when developing viral therapeutics. During docking, the virus particle identifies specific sites on the cell and binds to them. With Zika infection, docking then initiates the cell to take the virus in via an endosome - a separate compartment within the cell body. Proteins within the virus coat undergo structural changes to fuse with the membrane of the endosome, thereby releasing the virus genome into the cell, and completing the fusion step of infection.
Using a method called cryoelectron microscopy, which allows for the visualization of extremely small particles and their interactions, the team visualized C10 interacting with the Zika virus under different pHs, so as to mimic the different environments both the antibody and virus will find themselves in throughout infection.
They showed that C10 binds to the main protein that makes up the Zika virus coat, regardless of pH, and locks these proteins into place, preventing the structural changes required for the fusion step of infection. Without fusion of the virus to the endosome, viral DNA is prevented from entering the cell, and infection is thwarted.
These findings suggest that C10 may be developed as a therapy for Zika infection, and should be further explored. In addition, disrupting fusion with C10 may prove to be more effective in preventing Zika infection compared with therapies that attempt to disrupt docking. This is because the fusion step is critical for Zika infection, while the virus may develop other mechanisms to overcome disruptions to the docking step. With the call for rapid development of Zika therapies, C10 has emerged as a front runner to answer this call.
The research is published in the journal Nature Communications.
Neutralization mechanism of a highly potent antibody against Zika virus
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