Infecting nearly every species on Earth with incurable diseases takes herpesviruses a lot of reproductive power. Cornell researchers have found a new way to cripple that power by locking up virus DNA inside its viral carriers, cutting infectiveness by a factor of up to 10,000. Published in Journal of Virology in July, the study opens a much-needed new pathway for antiviral drug development.

As many as 95% of adults in the United States contract a herpesvirus by the age of 40, according to the Centers for Disease Control. Effects include cold sores, chicken pox, shingles, mononucleosis, blindness, birth defects, encephalitis, cancer, and transplant rejection. The virus can be fatal to babies; animals; and people living with HIV, undergoing chemotherapy, or relying on organ transplants.

“Giving antivirals is critical to transplant recipients and babies whose mothers have active infections—herpes kills 2,000 babies a year in the U.S. alone,” said James Law Professor of Virology Dr. Joel Baines, whose research associate Dr. Kui Yang led the study. “Viruses develop drug resistance just like bacteria do. This discovery offers a new tactic in the arms race against herpes.”

Yang and Baines discovered how virus particles (virions) assemble themselves to hold and release their DNA. A virus infection is like an army making tanks to invade and hijack an enemy fleet. Inside each virion, viral DNA waits in a sealed compartment called a capsid, waiting for the opportune time to emerge from the capsid and enter the host cell’s nucleus.

However, for DNA to squeeze into the capsid to begin with it must pass through the portal vertex—a screw-shaped portal protein containing an internal channel through which the DNA passes.  Connecting this protein to material making up the capsid’s walls is the first step to assembling the whole capsid, and eventually, the virion tank.

“We’ve been looking at this vertex for ways to stop virion assembly,” said Baines. “Our previous work found that a peptide, or mini-protein, binds to the vertex then connects similar proteins to form capsid walls. This study tested the idea that adding the peptide in excess would block capsid assembly. We reduced viral infectiveness over 1,000 fold—but the reason for it was the opposite of what we expected.”

Using electron microscopy, they saw that adding more of the peptides didn’t keep virions from assembling.

Instead, extra peptides bound to the portal vertex, locking the opening and trapping viral DNA inside the capsid. Normally the peptide exits the capsid once its construction job is complete, but adding it back during early infection plugs up the portal. Without the ability to release DNA, virions could not hijack host cells or spread infection.

“This aspect of viral replication has never been targeted by an antiviral before,” said Baines. “It’s a basic part of how all herpesviruses work. They all have very similarly structured capsids, portals, and peptides. So it’s possible that this portal-plugging principle could work on a variety of herpesviruses, providing a new approach to drugs combating the whole spectrum of herpesviruses across species.”