July 14, 2008

Learning How Cold Sore Viruses Hide

Microscopic image of the herpes virus

Once you’ve been infected with a herpesvirus, like the virus that causes cold sores, it takes up permanent residence in your body, hiding quietly in your nerve cells until the next outbreak. Now scientists say they’ve discovered tiny molecules that seem to help the cold sore virus stay inactive and protected. The finding may eventually lead to new strategies for treating these persistent infections.

Herpes simplex virus 1 (HSV-1) infects more than half of the U.S. population by the time they reach their 20s. Though it often causes no symptoms, for some the virus produces painful and unsightly cold sores, or fever blisters, that last for a week or more, usually in or around the mouth. The symptoms gradually fade as the virus retreats into the facial nerves beneath the skin. But stressors—like emotional upset, sunlight or fever—can reactivate HSV-1 later and lead to new sores in the same location as before.

To better understand how the virus hides away in nerve cells, Dr. Bryan R. Cullen of Duke University Medical Center and Dr. Donald M. Coen of Harvard Medical School led a team that looked at the products of HSV-1 genes during this inactive, or latent, phase. Their research was funded by NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and National Institute of General Medical Sciences (NIGMS).

The researchers focused on a small strand of RNA called the latency-associated transcript (LAT), which is the primary molecule generated by the inactive virus. Unlike most other viral RNAs, LAT apparently does not encode proteins. Its function has been something of a mystery.

In the July 2, 2008, online edition of Nature, the scientists showed that LAT can break down in human cells into even smaller strands called microRNAs. In cultured cells, one of these microRNAs was able to block production of the viral proteins needed for HSV-1 replication. Additional analyses found that at least 3 other microRNAs derived from LAT might also help to suppress normal HSV-1 operations.

The researchers turned to mice with latent HSV-1 infections to see if these same microRNAs existed in the nerve cells of living, infected animals. Indeed, all 4 of the LAT-derived microRNAs were found in the nerve cells, as was a 5th microRNA that comes from a yet-unknown source. This 5th microRNA inhibits production of a viral protein that helps HSV-1 genes function during an active infection.

Now that they’ve identified molecules that seem to keep the virus dormant, the researchers are searching for potential drugs that specifically bind to these microRNAs. By chasing the virus from hiding, the scientists hope to make it more vulnerable to drugs that target active, replicating HSV-1. “Inactive virus is completely untouchable by any treatment we have,” said Cullen. “Unless you activate the virus, you can't kill it.”

The scientists say their findings may also be relevant to other latent herpesviruses, including the varicella zoster virus, which causes chickenpox but sometimes reemerges as shingles, or herpes simplex virus-2, which causes genital herpes.

—by Vicki Contie

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