Intriguingly, this finding could also have huge implications for chemotherapy.
There’s no shortage of folks who’ve dealt with those annoying cold sore outbreaks caused by the herpes virus — it’s estimated that over half of the US population is infected. The virus tricks the immune system by outsmarting the body’s regular response that allows immune cells to recognize and destroy foreign invaders. However, scientists have never understood how the herpes simplex 1 virus pulls this trick off. Until now.
For the first time, a team of structural biologists in Jue Chen’s Laboratory of Membrane Biology and Biophysics captured atomic images of the herpes virus in action. The images show how the virus inserts itself into another protein, called TAP, in order to cause a “traffic jam” in an “important immune system pathway,” according to the press release.
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"This work illustrates a striking example of how a persistent virus evades the immune system," says Chen. "Once this virus enters the body, it never leaves. Our findings provide a mechanistic explanation for how it's able to escape detection by immune cells."
Usually when a virus invades a cell, it gets chewed up and little pieces become stuck to the outside of the cell. "These pieces act like a barcode to immune cells, which sense that a pathogen is present, and attack," says senior research associate and first author of the paper, Michael Oldham.
An important player in the process of getting the pieces of the virus to the cell’s surface is a protein called TAP — it’s a transporter that helps alert the immune system that the virus is hiding within a cell. Now, the researchers have photographic evidence that herpes tricks the immune system by messing with TAP.
Photo Credit: Laboratory of Membrane Biology and Biophysics at The Rockefeller University/Nature
"We knew that TAP was involved in our inability to have an effective immune response to this virus, but no one really knew what TAP looks like, or how it works," says Chen. "Our findings show exactly how this viral protein jams TAP, which has two effects. One, it precludes the regular protein from binding. Two, it makes the transporter stuck in this conformation."
Although scientists knew TAP was involved somehow, it’s extremely difficult to study since the samples are usually unstable and disintegrate easily. However, the researchers in this study used a technique called cryo-electron microscopy, which stabilizes the sample by freezing the purified protein in a thin layer of ice.
Finally understanding how the herpes virus tricks the immune system is a significant step forward, but the researchers say that therapeutics to prevent cold sores isn’t something to expect in the near future. Accidentally interfering with transporters in our body, like TAP, could likely end up disrupting many cellular processes and having major unintended side effects.
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However, there is an exciting take-away from the research: understanding the ways in which viruses block transporters could be used to treat other diseases.
Transporters like TAP often pump chemotherapy drugs out of the compartments in which they’re needed, which then renders the drugs useless. The researchers say that inhibiting these transporters for short periods of time could allow the chemotherapy to remain in the parts of the body where it’s needed and function effectively.
"We haven't been able to figure out how to block these transporters ourselves, so we are learning how it's done from viruses,” says Chen, “which we hope will teach us some strategies for inhibition."
