Herpes latency makes 'anti-sense.'

Herpes latency makes "anti-sense'

A backwards genetic message may be the reason why herpes simplex viruses lie dormant between occasional attacks on their human hosts, scientists reported this week. Because such latency periods are characteristic of genital herpes and cold sores, as well as some other viral diseases like AIDS and shingles, the researchers say that further studies on the unusual gene may suggest a way to keep inactive those viruses that persist in the human body.

It is well established that once a person is infected with herpes simplex type 1 viruses, the viruses "rest'--or at most grow very slowly--somewhere in the nerves throughout life, waiting to reactivate and ambush the host with painful attacks. Why and how the viruses remain inactive is of considerable interest in terms of public health: Between 65 and 80 percent of the general U.S. population has been exposed to these herpes viruses.

Scientists at the National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Md., hunted for dormant herpes simplex viruses in facial nerve tissue taken from cadavers that did not have signs of active herpes infections. The NIAID group found large amounts of RNA similar in structure to a previously identified viral gene that forces infected host cells to produce a viral protein called ICP0 and helps regulate subsequent steps in viral replication. But there was a twist: The new RNA was a mirror image of the ICP0 gene, and therefore is what geneticists call "anti-sense' RNA.

The NIAID researchers, with collaborators from the Office of the Chief Medical Examiner in Baltimore, say in the Dec. 3 NEW ENGLAND JOURNAL OF MEDICINE that the anti-sense RNA may cause latency by either blocking activity of the normal viral RNA, or coding for a protein that interferes with virus growth. Kenneth D. Croen of NIAID said in an interview that the current results may suggest "the ideal therapy' for the millions who suffer from herpes infections. "It really depends on whether the anti-sense [RNA] is a regulatory [message] itself, or whether there is a regulatory protein produced,' he explains. "In either case, one could devise therapeutic approaches' that essentially duplicate either action. If the RNA turns out to be a regulator, it would be the first time such a mechanism would be demonstrated outside bacteria.

The current study is an extension of work in laboratory mice reported earlier this year by University of California researchers in Los Angeles and Irvine. Results from human tissues, however, should accelerate herpes research by providing "a uniform model of herpes simplex latency,' says Croen. "In the animal models for herpes, it's less clear what latency is,' he says. "It is not known whether the viral [genetic machinery] is shut off in animals.'

More experiments must be done, says Croen, to prove whether the anti-sense RNA is really the key factor in establishing and maintaining latency, and whether it comes from the virus. The approach also may be useful in studying factors like stress, which is known to reactivate the herpes virus (see p.360), and in studying latency in other viral infections.