New strategy for antibodies to disable viruses

It is widely understood that antibodies neutralize viruses by latching onto their surfaces and blocking them from infecting host cells. But new research reveals that this barrier method isn’t the only way that antibodies disable viruses. An international team of researchers has discovered that antibodies also distort viruses, thereby preventing them from properly attaching to and entering cells.

“Everybody thinks of antibodies as binding to viruses and blocking them from entering cells — essentially locking them down,” said the senior author. “But our research reveals for the first time that antibodies may also physically distort viruses, so they are unable to properly attach to and infect host cells.”

In their study, which published in the journal Cell, the authors investigated the interactions between human monoclonal antibody (HMAb) C10 and two disease-causing viruses: Zika and dengue. The HMAb C10 antibodies they used had previously been isolated from patients infected with dengue virus and had also been shown to neutralize Zika virus.

The researchers used a combination of techniques, including cryogenic electron microscopy (cryo-EM) to visualize the viruses and hydrogen/deuterium exchange mass spectrometry (HDXMS) to understand their movement.

To document the effects of antibodies on Zika and dengue viruses, the team collected cryo-EM snapshots of the viruses under conditions of increasing concentrations of antibodies.

In parallel, the team applied HDXMS, a technique in which molecules of interest — in this case Zika and dengue virus, along with HMAb C10 antibodies — are submerged in heavy water. Heavy water, the author explained, has had its hydrogen atoms replaced with deuterium, hydrogen’s heavier isotopic cousin.

“When you submerge a virus in heavy water, the hydrogen atoms on the surface of the virus exchange with deuterium,” the author said. “You can then use mass spectrometry to measure the heaviness of the virus as a function of this deuterium exchange. By doing this, we observed that dengue virus, but not Zika virus, became heavier with deuterium as more antibodies were added to the solution. This suggests that for dengue virus, the antibodies are distorting the virus and allowing more deuterium to get in. It’s as if the virus is getting squished and more surface area becomes exposed where hydrogen can be exchanged for deuterium.”

In contrast, Zika virus did not become heavier when placed in heavy water, suggesting that its surface, while fully occupied by antibodies, is not distorted by the antibodies.

By combining cryo-EM and HDXMS, the team was able to get a comprehensive picture of what happens when antibodies attach to Zika and dengue viruses.

In fact, the team found that at saturating conditions, in which antibodies were added at high enough concentrations to fill all the available binding locations on the dengue viruses, 60% of the virus’ surfaces became distorted. This distortion was enough to protect the cells from infection.

Indeed, when the scientists incubated the antibody-bound dengue viruses with BHK-21 cells, a cell line from the kidneys of baby hamsters that is often used in viral infection research, they found that 50-70% fewer cells were infected.

The author explained that with some viruses, including Zika, antibodies work by jamming the exits so the passenger cannot get out of the car. We have found a new mechanism in dengue virus whereby antibodies basically total the car so it cannot even travel to a cell.”

The author explained that contrary to the now-familiar SARS-CoV-2, which has spike proteins protruding in all directions, the surfaces of both Zika and dengue is a smoother surface with peaks and valleys. For dengue virus, antibodies especially prefer binding the ‘peaks’ known as 5-fold vertices. Once all the proteins on the 5-fold vertices have been bound, antibodies will turn to their second-favorite peaks — the 3-fold vertices. Finally, they are left with only the 2-fold vertices.

“Antibodies do not like two-fold vertices because they are very mobile and difficult to bind to,” said the author. “We found that once the 5- and 3-fold vertices have been fully bound with antibodies, if we add more antibodies to the solution, the virus starts to shudder. There’s this competition taking place between antibodies trying to get in and the virus trying to shake them off. As a result, these antibodies end up burrowing into the virus rather than binding onto the 2-fold vertices, and we think it’s this digging into the virus particle that causes the virus to shake and distort and ultimately become non-functional.”

The author explained that Zika is a much more stable, less dynamic virus than dengue, which has a lot of moving parts.

“Dengue and Zika look similar but each one has a different give. Dengue may have evolved as a more mobile virus as a way of avoiding being caught by antibodies. Its moving parts confuse and throw off the immune system. Unfortunately for dengue, antibodies have evolved a way around this by burrowing into the virus and distorting it.”

It appears that the same type of antibody can neutralize Zika and dengue in two different ways — one where it binds to the virus and deactivates it, which is the traditional way we think about antibody activity, and the other where it burrows in and distorts the virus.

“HMAb C10 antibodies are specific to dengue and Zika viruses, and happen to be capable of neutralizing Zika and dengue viruses in two different ways,” the authorsaid. “But you could potentially design therapeutics with the same capabilities for treating other diseases, such as COVID-19. By creating a therapeutic with antibodies that can both block and distort viruses, we can possibly achieve greater neutralization.”

The author added, “You don’t want to wait for a virus to reach its target tissue, so if you can introduce such a therapeutic cocktail as a nasal spray where the virus first enters the body, you can prevent it from even entering the system. By doing this, you may even be able to use less antibody since our research shows that it takes less antibody to neutralize a virus through the distortion method. You can get better bang for the buck.”