Unmasking Herpes: New Research Sheds Light on Drug Resistance
Herpes simplex virus (HSV) affects over half the world’s population, lurking silently within our nerve cells. For most, it causes occasional, mild outbreaks like cold sores. But for some, HSV can lead to more serious, persistent infections that resist treatment.
Scientists have long known that mutations in the virus’s polymerase, the enzyme responsible for replicating its DNA, can lead to drug resistance. Antivirals like acyclovir and foscarnet, the two main weapons against HSV, are becoming increasingly ineffective as the virus mutates.
Now, researchers led by Jonathan Abraham, a virologist at Harvard Medical School, have made significant progress in understanding how these mutations occur. Using a technique called cryo-electron microscopy, they captured images of the HSV polymerase in action, both with and without antiviral drugs present.
"Although most people think of herpesviruses as causing cold sores," Abraham explained, "they can lead to severe brain infections. Severe cases I’ve seen as a doctor have always had me thinking, ‘What can we do in the lab?’"
Imagine the polymerase as a hand, with the active site where DNA replication happens nestled in the palm. The fingers of this hand move around to grip the DNA.
Abraham and his team discovered that resistance mutations don’t necessarily occur at the drug binding site itself. Instead, they alter the flexibility and movement of the polymerase’s fingers. These mutations essentially make the virus more nimble, allowing it to evade the drugs’ grasp.
"It’s not necessarily the shape of the hand or where the drug binds that determines resistance," Abraham clarified. "Rather, it’s differences in how these enzymes move."
This groundbreaking research signals a potential shift in the fight against HSV.
"Polymerase resistance via protein changes is a common way of avoiding drug potency," said Adrian Wildfire, a virologist and drug development specialist at IQ-IDM.
He believes this new understanding could pave the way for developing novel drugs that lock HSV polymerase into a static conformation, effectively neutralizing its ability to mutate and become resistant.
While promising, there’s still more work to be done.
"In the real world, resistance is rarely absolute," nodded Abraham. "What are the implications of three-fold versus two-fold versus 1.5-fold inhibition? We don’t know yet.”
The ultimate goal is to develop algorithms that can accurately predict protein movement and forecast resistance in clinical settings, allowing for personalized and more effective treatment strategies.
