by Rideeta Raquib ’19

The Zika virus, or ZIKV, falls under the classification of the flavivirus genus, which includes Dengue and West Nile virus members, and can lead to numerous negative side effects. The virus contains a surface that is composed of 180 copies of E protein organized in an icosahedral symmetrical pattern with 60 asymmetric units. It also contains three domains, DI, DII, and DIII. DIII is the fusion of the virus with endosomal membrane during entry into cell. The fusion occurs in multiple steps, whereby the E protein virus has to bind to cell receptors and cause endocytosis. Furthermore, the low pH of endosomes causes the E protein to flip so that it exposes fusion loops, trimeric structures, and the conformational changes initiated by DIII that allow for fusion to occur.    

A team of researchers from Duke-NUS Medical School analyzed the antibodies that have shown effectiveness in treating Dengue.  C10 was found to have the ability to prevent antibody dependent enhancement (ADE) of the infection in myeloid cells caused by Dengue. In the ADE model, myeloid cells are resistant to ZIKV infection, thus the receptor is not present. The addition of Dengue human serum showed infection enhancement, whereby the antibodies attached to ZIKV has the ability to bind to Fc receptors in myeloid cells, thus ZIKV doesn’t need to bind directly to the receptor. Human monoclonal antibodies (HMAb), which are clones of immune cells generated from a parent cell that binds to the same antigen, have not been tested against ZIKV. The addition of HMAb to C10 forms an antibody that also attaches to Fc receptors, but it neutralizes the virus after the attachment. Fragment-antigen binding (Fab), the variable region that consists of the antigen binding site and the specific mechanism to the virus at that site, was observed to have the ability to block the virus surface protein at the pH of 5 and 6.5. Thus ensuring that reorientation of E protein so that fusion doesn’t occur.

These interesting findings will enable scientists to discover novel therapeutic approaches to ZIKV by employing C10. With Zika spreading, C10 might be one of the best initial solutions to combat the issue.

References:

1. S. Zhang, et al., Neutralization mechanism of a highly potent antibody against Zika virus. Nature Communications 7, (2016). doi: 10.1038/NCOMMS13679.
2. Image retrieved from: http://www.saudemedicina.com/wp-content/uploads/2015/05/zika-virus.png