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Partners Take Major Step in Long-Running Study of Herpes Simplex
Published July 2009
Throughout a collaboration of almost 20 years, Richard Thompson, PhD, and Nancy Sawtell, PhD, have worked to gain insight into how the herpes simplex virus (HSV) exits latency and causes recurrent disease.
They have taken a major step forward with publication of research in the journal PLoS Pathogens that identifies a viral protein, VP16, as the molecular key that must be produced before the virus can exit the latent state in neurons.
The discovery could lead to improved HSV vaccines and treatments, the investigators say.
"This has really altered the way we think about exiting latency," says Thompson, a professor in the department of molecular genetics, biochemistry and microbiology at UC.
"Formerly, researchers had this idea that it would be like a light switch--that you'd get under stress and then the switch would come on and it would turn on a specific viral gene, and that would cause the virus to reactivate.
"But it's not a light switch--it seems that stress increases the probability of the de-repression of VP16 that results in reactivation."
HSV-1, usually acquired during childhood, is the leading cause of blindness and acute sporadic encephalitis in the United States. The most common symptoms of infection, however, are recurrent lesions called cold sores or fever blisters, because fever has long been known to induce HSV reactivation.
The two distinct lifestyles of HSV--active and latent--were first proposed 80 years ago. The virus replicates itself at the body surface, producing thousands of copies that can be transmitted to other people.
In neurons, however, the virus can enter a latent state where the viral genetic code can be maintained for the lifetime of the infected person, retaining the potential to exit latency and reactivate.
"Our findings show that, in elegant simplicity, the herpes simplex virus regulates this complex lifecycle through the expression of VP16," says Sawtell, a researcher in the division of infectious diseases at Cincinnati Children's Hospital Medical Center and an associate professor in UC's pediatrics de-partment.
Funding support for the study, which was conducted in collaboration with the Medical Research Council Virology Unit of Glasgow, Scotland, came from the National Institutes of Health.
Using a technique developed by Sawtell, the research team infected mice with mutated forms of herpes virus--one carrying a functional form of VP16 and one carrying an inactive form.
After the initial infection faded, the researchers raised the body temperature of the mice and observed how many had a recurrence of viral outbreak.
The mice with the inactive form of VP16 did not undergo a reactivation of the virus, while the mice with the functional form did, indicating that VP16 is the key to reactivation. They found that reactivation was blocked at the earliest stage.
"So what we've learned from the animal models is that there is this level of spontaneous reactivation," Sawtell says.
"We don't know exactly how stress keys into the latent viral genome and leads to an increase in reactivation frequency. But now that we know what the viral protein is, we can try to understand what it is that's unique in the promoter that's interacting with the host."
Using such knowledge, improved vaccines and treatments could be developed that could potentially block reactivation before the viral protein is expressed.
"I can't think of a better dueling partner than this virus in terms of challenging you," Sawtell says. "Every time you think you're going to figure it out, it throws another stumbling block."
Adds Thompson: "Every five years, we thought we were really close. And now we've got a really nice piece of it."