A single viral protein enables dormant herpes virus to wake up, suggests a study appearing online March 26 in PLoS Pathogens. The protein, called VP16, acts as the gatekeeper for the damaging, infective activity of the virus, new results in mice show.
Figuring out what causes an inactive, latent state to become a highly infectious state is “very, very important for understanding this virus,” says study coauthor Nancy Sawtell of Cincinnati Children’s Hospital Medical Center in Ohio. The results may lead to a better way to control herpes simplex virus type 1, a virus carried by more than 70 percent of the human population, Sawtell says.
Infection with the herpes simplex virus usually triggers an acute phase that may be accompanied by a fever and cold sores. Then the symptoms subside, but the virus retreats and hides in the trigeminal ganglia, a cluster of nerve cells near each ear in people. Once ensconced in nerve cells, the virus never goes away. “If I can borrow a line from the diamond people, herpes is forever,” says Steven Triezenberg, a researcher at the Van Andel Institute in Grand Rapids, Mich.
The most common symptoms of infection are embarrassing and unpleasant sores on the lips, mouth and face. But the virus can also have severe consequences: Herpes simplex virus type 1 is the leading cause of infectious blindness and can be deadly to babies who pick up the virus during birth.
Stress, sunburns and fevers can rouse the latent virus and cause sores (hence the name fever blisters), but the details of how the virus can come out of hibernation has been a mystery. The new research in mice finds that a previously discounted protein known to play a role in the initial infection — VP16 — is the key.
In the new study, mice were infected with herpes virus carrying a mutated, inactive form of VP16. After the initial infection had faded, the researchers stressed the mice by raising body temperature and watched to see how many mice had a recurrence of a viral outbreak. The researchers used a new technique to monitor viral gene activity and viral proteins in individual nerve cells. Stress did not reactivate the virus in these mice.
But in mice infected with herpes carrying the functional form of VP16, the virus came roaring back, suggesting that VP16 is the key to reactivation.
In addition to pinpointing VP16 as a key player in reawakening the virus, the new study also shows that the VP16 gene becomes active much earlier in the reactivation than it does in the initial infection. The VP16 protein is made by the active gene in a small number of neurons, which is enough to begin the cascade of infectivity anew. “This paper comes back to say VP16 is the first triggering event,” Triezenberg says.