A team led by led by Purdue University researchers is the first to determine the structure of the Zika virus, which reveals insights critical to the development of effective antiviral treatments and vaccines.
The team was led by Richard Kuhn, director of the Purdue Institute for Inflammation, Immunology and Infectious Diseases (PI4D) with Michael Rossmann, Purdue’s Hanley Distinguished Professor of Biological Sciences. Kuhn and Rossmann have studied flaviviruses, the family of viruses to which Zika belongs, for more than 14 years. They were the first to map the structure of any flavivirus when they determined the dengue virus structure in 2002. In 2003, they were first to determine the structure of West Nile virus and now they are the first to do so with the Zika virus.
The team identified regions within the Zika virus structure where it differs from other flaviviruses, the family of viruses to which Zika belongs that includes dengue, West Nile, yellow fever, Japanese encephalitis and tick-borne encephalitic viruses. The structure of the virus provides a map that shows potential regions of the virus that could be targeted by a therapeutic treatment. This will enable to create an effective vaccine or to improve our ability to diagnose and distinguish Zika infection from that of other related viruses. Determining the structure greatly advances the understanding of till now little known Zika virus. It illuminates the most promising areas for further testing and research to combat infection.
A paper detailing the findings was published on March 31 in the journal Science and is available online.
- Cryo-electron microscopy: It enabled to determine the virus structure at a resolution that previously would only have been possible through X-ray crystallography, especially for viruses like Zika that have a lipid membrane and don’t organise accurately in a crystal. Now, the virus can be viewed in a more native state.
- Near-atomic resolution: The team studied a strain of Zika virus isolated from a patient infected during the French Polynesia epidemic and determined the structure to 3.8Å. At this near-atomic resolution, the key features of the virus structure can be seen and groups of atoms that form specific chemical entities, such as those that represent one of 20 naturally occurring amino acids, can be recognised.
- Similarity to other flaviviruses: The team found the structure to be very similar to that of other flaviviruses with an RNA genome surrounded by a lipid, or fatty, membrane inside an icosahedral protein shell. The strong similarity with other flaviviruses was not surprising and is perhaps reassuring in terms of vaccine development already underway, but the subtle structural differences are possibly the key.
- Areas of structural difference: Most viruses don’t invade the nervous system or the developing foetus due to blood-brain and placental barriers, but the association with improper brain development in foetuses suggest Zika does. It is not clear how Zika gains access to these cells and infects them, but these areas of structural difference may be involved. These unique areas may be crucial and warrant further investigation.
- Glycosylation site: The glycosylation site where Zika virus differs from other flaviviruses protrudes from the surface of the virus. A carbohydrate molecule consisting of various sugars is attached to the viral protein surface at this site. In many other viruses, it has been shown that as the virus projects a glycosylation site outward, an attachment receptor molecule on the surface of a human cell recognises the sugars and binds to them. The glycosylation site and surrounding residues on Zika virus may also be involved in attachment to human cells, and the differences in the amino acids between different flaviviruses could signify differences in the kinds of molecules to which the virus can attach and the different human cells it can infect. If this site functions as it does in dengue and is involved in attachment to human cells, it could be a good spot to target an antiviral compound. If this is the case, perhaps an inhibitor could be designed to block this function and keep the virus from attaching to and infecting human cells.
- Further testing: The team plans to pursue further testing to evaluate the different regions as targets for treatment and to develop potential therapeutic molecules.