How does herpes virus become resistant to antivirals?

Researchers in the US believe they have found the mechanism which prevents anti-herpes drugs from working in some people.

With repeated use there is a risk that antiviral drugs, which are usually helpful in treating herpes simplex virus (HSV), can become ineffective if the virus changes and acquires resistance to the treatment.

HSV-1, the main cause of oral herpes, affects an estimated 3.7 billion people under 50 globally. An estimated 491 million have HSV-2, the main cause of genital herpes.

While HSV is not curable, it is treatable. Acyclovir is the leading treatment and foscarnet is used as a second-line treatment for drug-resistant infections.

Now a Harvard University team has revealed one of the ways HSV can acquire resistance to these antiviral medications, which could lead to better outcomes for patients.

The new Cell study shows that parts of DNA polymerase, an enzyme used by the virus to replicate itself, move into different positions when carrying out its function, altering its susceptibility to drugs that are supposed to bind and inhibit it from working.

This raises the possibility of using drugs to block or freeze these conformational changes as a strategy for overcoming drug resistance.

Senior author Jonathan Abraham, associate professor of microbiology at Harvard Medical School and infectious disease specialist at Brigham and Women’s Hospital, says: “Over the years, the structures of many polymerases from various organisms have been determined, but we still don’t fully understand what makes some polymerases, but not others, susceptible to certain drugs.

“Our study reveals that how the different parts of the polymerases move, known as their conformational dynamics, is a critical component of their relative susceptibility to drugs.”

A protein is made of a chain of amino acids that fold into a 3-dimensional structure known as its native conformation. For DNA polymerase, this resembles a right hand, with palm, fingers, and thumb domains that each carry out different, critical functions.

But this 3D structure isn’t static. Different parts can move when in contact with other cellular components or through external influences, such as changes in pH or temperature. 

For example, the fingers of a polymerase protein can open and close like the fingers of a hand. It can only replicate DNA when the fingers are closed.

Abraham and colleagues used cryo-electron microscopy (cryo-EM) – bombarding frozen HSV-1 polymerase samples with beams of electrons – to get high-resolution images of its structure in multiple conformations, as well as when bound to acyclovir and foscarnet.

Until now, scientists believed that polymerases closed partially only when they attached to DNA and closed fully only when they added a DNA building block (a deoxynucleotide).

This study found that HSV polymerase can fully close just by being near DNA. This makes it easier for acyclovir and foscarnet to latch on and stop the polymerase from working, halting viral replication. 

The findings also suggest that mutations far away from the drug binding sites confer antiviral resistance by altering the position of these polymerase fingers.

“I’ve worked on HSV polymerase and acyclovir resistance for 45 years,” says study co-author Donald Coen, professor of biological chemistry and molecular pharmacology at HMS.

“Back then I thought that resistance mutations would help us understand how the polymerase recognises features of the natural molecules that the drugs mimic.

“I’m delighted that this work shows that I was wrong and finally gives us at least one clear reason why HSV polymerase is selectively inhibited by the drug.”

Imma Perfetto writes regularly about microbiology, genetics, and immunology, and has a feature on how protein folding works, in the forthcoming Spring edition of Cosmos Magazine.