Wake up and die

DURHAM, N.C.—Duke University Medical Center scientists report that they have discovered how the herpes simplex virus 1 that causes cold sores remains dormant and hidden, and that they may also have a way to "wake it up and kill it," as a recent Duke news release about the research puts it.

"We have provided a molecular understanding of how HSV1 hides and then switches back and forth between the latent and active phases," says Bryan Cullen, Duke professor of molecular genetics and microbiology.

Most of the time, he notes, HSV1 lives quietly for years in the trigeminal nerve of the face until triggered to reawaken by excessive sunlight, fever or other stresses—and thus it largely remains out of reach of any effective therapies. During the dormant period, HSV1 does not replicate itself and only produces one molecular product, called latency associated transcript RNA (LAT RNA).

Cullen says that it has "always been a mystery" what LAT RNA does. "Usually viral RNAs exist to make proteins that are of use to the virus," he adds, "but this LAT RNA is extremely unstable and does not make any proteins."

In mice, the Duke team showed that the LAT RNA is processed into smaller strands of microRNAs that block production of the proteins that make the virus initiate active replication. As long as the supply of microRNAs is sufficient, the virus stays dormant.

After a larger stress, however, the virus starts making more messenger RNA than the supply of microRNAs can block, and protein manufacturing begins again. This tips the balance, and the virus ultimately makes proteins that begin active viral replication. These findings were recently published in the journal Nature.

Other herpes viruses also make significant use of microRNAs, but in a different way in many cases, so Cullen doesn't necessarily think his team's findings have a wider application for all herpes, particularly not for Epstein-Barr virus, cytomegalovirus, or the herpes viruses associated with roseola or Kaposi's sarcoma.

But there are very likely insights that can be applied in developing treatments for herpes simplex virus 2, which affects the genitals, and possibly for herpes zoster as well, which causes chickenpox and can resurface in adulthood to cause shingles.

The approach to curing HSV1, and possibly HSV2 and herpes zoster, would be a combination therapy, Cullen says, adding, "Inactive virus is completely untouchable by any treatment we have. Unless you activate the virus, you can't kill it."

So, he and his team are testing a new drug designed to very precisely bind to the microRNAs that keep the virus dormant. If it works, the virus would become activated and start replicating. Once the virus is active, a patient would then take acyclovir, a drug that effectively kills replicating HSV1.

"In principle, you could activate and then kill all of the virus in a patient," Cullen says. "This would completely cure a person, and you would never get another cold sore."

He and the team are now working with drug development companies in animal trials to begin to answer questions about how to deliver such a drug most effectively. DDN