Deconstructing Dengue

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Immunity to the dengue virus (shown above) is shaped by an epitope found in a hinge region of the virus’ glycoprotein envelope (Image source: http://www.pnas.org)

A study published in this past week’s PNAS has found the sweet spot for conferring long-term immunity against the dengue virus. Researchers found that this sweet spot, a hinge region found in the virus’ outer envelope, is what macaque and human antibodies respond to years after initial infections, and is different for each of the virus’s serotypes.

The dengue virus comes in four flavors, called DENV-1, -2, -3, and -4. Immunity from exposure to one of these serotypes is not transferrable to another. In fact, according to the World Health Organization’s guidelines for treating the virus, being immune to, say, DENV-2 will actually enhance the viral effects of other serotypes.

Dengue is a heavy hitter in tropical and subtropical regions, with an estimated 390 million infections every year according to a study from 2013. The virus is transmitted through varying Aedes species of mosquitoes, and primates are the only known vertebrate hosts.

Developing a vaccine against the virus has been a slow process, largely because researchers had not fully established what parts of the virus antibodies reacted to (these parts are called epitopes, if you’re at all curious). This new study examined how the glycoprotein that makes up the virus’ envelope might fit into those immune responses.

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Dengue is found in tropical and subtropical regions and clocks in at 390 million infections every year, of which about 96 million manifest with symptoms (Image source: denguemu.wordpress.com)

The group focused on the hinge between the first and second domains of the virus’ envelope. Using a combination of genetics and synthetic biology, they transferred this hinge region from the DENV-4 serotype to the DENV-3, making a DENV-3/4 hybrid.

They introduced this new chimeric virus into macaques that had already been infected (and thus were immune to) DENV-3. Since the only new part of the virus’ envelope was the hinge, if there was a change in response it must originate there. They found that this new hybrid was no longer sensitive to DENV-3 specific antibody responses. Instead, their hybrid was now sensitive to DENV-4 specific antibodies, meaning these long-term immune responses were targeting the hinge region the group had swapped out.

Knowing that the hinge region is what defines long-term immunity and that those regions can be swapped between serotypes could move the development of novel vaccines forward, perhaps towards cross-protective vaccines. As the authors point out, more work needs to be done to fully understand how the immune system interacts with the rest of the viral envelope, to try and find some way of targeting the dengue virus in a way that will target all four serotypes.

But their findings are very important in understanding how and why the vaccines we have now work as well as they do, and where they fall short. Their technique of swapping epitopes between viruses also has a much broader impact that could help in designing vaccines for other viruses like Hepatitis C or HIV.

Original article:

http://www.pnas.org/content/111/5/1939.full

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