New Hope Against the Cold Sore Virus

WEDNESDAY July 2, 2008 -- Millions of Americans are afflicted by breakouts of unsightly cold sores, caused by the herpes simplex 1 virus, but new research is finally offering them the possibility of a cure.

Scientists at Duke University say they've unlocked the mystery of how herpes simplex 1 slips into dormancy and stays dormant -- evading the drugs that might otherwise wipe it out.

Buoyed by that finding, the same team is testing an experimental agent that can "reawaken" the virus, so it might be flushed out into the open and eradicated.

The hope is that, "we could use the drugs that we already have, plus an effective immune system, to cure a person from infection," explained lead researcher Jennifer Lin Umbach, a postdoctoral associate in Duke's department of molecular genetics and microbiology.

She and her colleagues published their findings July 2 in the online edition of Nature.

According to the American Social Health Association, up to 80 percent of American adults are infected with herpes simplex 1. Many, but not all, will suffer outbreaks involving unsightly, painful sores around the lips and mouth.

Certain drugs, such as the antibiotic acyclovir, can help prevent or curb outbreaks, but there is no way of eliminating the virus, and infection typically lasts a lifetime.

Between outbreaks, herpes simplex 1 enters long periods of "latency," hiding inside neurons within the face's trigeminal nerve. In this state, the virus is largely inactive and invulnerable.

"There's no way for either the drugs that we have or for our immune systems to recognize the virus or do anything about it," Umbach explained.

During outbreaks some, but not all, of the viral particles do reactivate and replicate. Scientists have long sought a method of driving all of the virus out of latency at once, so it could then be eliminated with existing drugs.

However, until now, no one even understood how herpes simplex 1 maintained its latent state.

That's all changed, thanks to the painstaking research conducted at Duke. According to Umbach, scientists had long noted that during latency, herpes simplex 1 produces only one tiny product, dubbed "latency associated transcript RNA" (LAT RNA).

These bits of genetic material didn't seem to have any useful function. However, after careful research, the Duke team found that this gene "is processed into smaller parts called microRNAs, and those microRNAs are actually used to target the genes that are required for active replication," Umbach said.

In other words, over weeks or even years, dormant herpes simplex 1 quietly generates just enough LAT RNA to act as a kind of "damper" on the genetic switch that would normally push it into full activation.

"So, the genes for active replication stay asleep -- until this gene is interrupted somehow," Umbach said.

This, then, appears to be the elusive mechanism by which herpes simplex 1 stays dormant and evades drug therapy.

The next step, according to Umbach, is to find an agent that blocks LAT RNA, thereby waking up the entire population of virus at once.

She said her team is already experimenting with an experimental drug that appears to do just that. Once this agent is inside the host nerve cell, "it binds to the microRNAs and inhibits their function," she explained. The virus is then allowed to activate. "Then one of the drugs like acyclovir should be able to handle the infection," Umbach said.

That strategy appears to be working in the test tube at least. "There are animal trials under way, and we are looking into clinical trials for humans. But it will be a while before we can get there," Umbach cautioned.

Another expert was also guardedly optimistic.

"This provides a new strategy to use for seeking a cure," said Christopher Beisel, a virologist and program officer at the U.S. National Institute of Allergy and Infectious Diseases, which funded the Duke research. "However, I always caution people that when something like this comes out, and people start talking about cures, that there's a long way to go, starting with animal experiments."

And Beisel noted that there's always an element of risk whenever doctors purposefully re-awaken a dormant virus. "You are bringing it forth with the possibility of causing disease and then having to stomp on it before it does. So, I am cautiously optimistic, but there are some problems to work out."

Nevertheless, the findings could apply to the whole range of herpes viruses, including herpes simplex 2, which causes genital herpes, and the varicella zoster virus, which causes chickenpox and a more chronic, painful condition known as shingles.

In fact, Umbach said, the Duke group plans to target the shingles virus in their next round of research.

Beisel agreed that the findings could have implications far beyond the common cold sore.

"I'm highly psyched about this as basic research," he said. "Just being able to understand what's going on with latency may have relevance to other herpes viruses."

More information

There's more on oral herpes at the American Social Health Association.

Posted: July 2008


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