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The Cold Sore's Clever Camouflage

31 May 2006 (All day)
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Dr. Herrmann/CDC

Break out.
Herpes simplex virus-1 lies dormant for years between episodes of cold sore misery.

The classic trick of herpes viruses is their ability to lay dormant in the body, undetected by the immune system, just waiting for the perfect opportunity to cause a new outbreak of cold sores, shingles, or mononucleosis. Now researchers have puzzled out the molecular ruse that allows the most common of these viruses--herpes simplex virus-1 or HSV-1--to remain undetected for years.

After an initial infection, HSV-1 goes into hiding in nerve cells, where it eludes the immune system's sentries. It shuts down all of its genes except one--a gene called the LATency-associated transcript (LAT). Scientists identified LAT more than a decade ago, and a few years later researchers showed that it works to prevent infected cells from dying by blocking apoptosis, the cell's program of ritual suicide. "Since then people have been looking for the protein [the gene makes], but have had no luck," says microbiologist Nigel Fraser at the University of Pennsylvania School of Medicine.

That's because researchers were looking for the wrong kind of molecule. The LAT gene codes not for a protein but for a short stretch of RNA, Fraser and his colleagues report online this week in Nature. This so-called microRNA disrupts the expression of two key cellular genes called TGF-β and SMAD3, in a process known as RNA interference (RNAi). Both genes help to regulate apoptosis, and limiting their expression helps to keep the infected cell alive. Moreover, the immune system homes in on foreign proteins, so by using RNA instead of a protein to keep the host cell going, the virus manages to evade detection.

Some virus experts had started to suspect that latent herpes viruses might use RNAi--a molecular trick that scientists first recognized a few years ago. But this work is the first direct evidence that it is true, says Judy Lieberman, an RNAi expert at Harvard Medical School. She says the find suggests a way to attack the virus even in hiding. Scientists have successfully targeted other virus-infected cells with RNAi she says, and there may be a way to thwart the interference of the LAT gene.

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