Researchers at Duke–NUS Medical School, in collaboration with a team at the University of North Carolina (UNC), have discovered the mechanism by which C10, a human antibody that reacts with the dengue virus, prevents Zika virus infection (ZVI) at the cellular level. The research was published in Nature Communications.
To infect a cell, virus particles usually undergo two main steps, docking and fusion, which are common targets for disruption when developing viral therapeutics. During docking, the virus particle identifies specific sites on the cell and binds to them. With ZVI, 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 the visualization of extremely small particles and their interactions, the investigators observed C10 interacting with the Zika virus under different pHs, which mimicked the environments in which the antibody and the virus function throughout an 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.
“Hopefully, these results will further accelerate the development of C10 as a Zika therapy to combat its effects of microcephaly and Guillain–Barré syndrome,” said lead investigator Dr. Shee-Mei Lok.
“By defining the structural basis for neutralization, these studies provide further support for the idea that this antibody will protect against Zika infection, potentially leading to a new therapy to treat this dreaded disease,” added Ralph Baric, PhD, a professor at UNC’s Gillings School of Global Public Health.
The new findings suggest that C10 may be developed as a therapy for ZVI and should be further explored, according to the investigators. In addition, disrupting fusion with C10 may prove to be more effective in preventing ZVI compared with therapies that attempt to disrupt docking. This is because the fusion step is critical for ZVI, whereas the virus may develop other mechanisms to overcome disruptions to the docking step.
Source: Duke–NUS Medical School; November 24, 2016.