Herpes simplex virus 1 (HSV-1), which causes cold sores, uses a short, double-stranded RNA to outwit a cell’s defensive measures. That’s why it can hang out in the body indefinitely, new research suggests. By disrupting this mechanism, scientists may eventually find a way to permanently eradicate herpes infections in people.
Both HSV-1 and its close relative HSV-2, which typically causes genital herpes, infect the nerve cells located outside the brain and spinal cord. Once a person becomes infected, HSV-1 and HSV-2 stick around in a dormant state and can intermittently cause breakouts in some people. The virus succeeds in its long-term residency because it prevents immune system prompts that usually lead virus-infected cells to sacrifice themselves, says microbiologist Nigel Fraser of the University of Pennsylvania School of Medicine in Philadelphia.
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Six years ago, a Los Angeles–based team of researchers discovered a viral gene that they named the latency-associated transcript gene (LAT). This gene seemed to control HSV-1’s capacity to lay low. However, after years of searching, scientists hadn’t located any LAT-encoded protein, which would offer clues to how the gene exerts its life-sustaining effect on cells.
Traditionally, scientists determine what protein a gene encodes by searching for the often-lengthy RNA transcript, which translates the gene’s information into its product. “People had been looking for these long [LAT] RNAs,” says Fraser.
However, some researchers took a different approach. They hypothesized that instead of a protein, LAT ‘s product is a microRNA—a tiny, double-stranded piece of RNA that a cell’s enzymes cut from a longer transcript. Recent research has suggested that cells and some pathogens use microRNAs to control a variety of cellular processes.
To investigate this hunch, Fraser’s team worked with lab-grown cells. In some of the cells, they shut off production of the dicer enzyme, which processes long strands of RNA into microRNAs. They then slipped LAT into all the cells.
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When the scientists doused the cells with a chemical that triggers cell suicide, those without the dicer enzyme died. Cells with dicer survived the chemical onslaught, suggesting that dicer processes the microRNA that gives the cells their staying power.
Next, the researchers used a computer program to scan LAT for sections that have sequences characteristic of microRNAs. The team inserted its leading-candidate microRNA into cells and then added the suicide-inducing chemical. Their small RNA snippet kept the cells alive, says Fraser.
In previous studies, researchers have shown that a small, double-stranded piece of RNA can sometimes muffle the effects of a gene that has a complementary sequence. This phenomenon is known as RNA interference (SN: 7/2/05, p. 7: Available to subscribers at Sound Off). To determine which gene or genes the LAT microRNA might be acting on, Fraser’s team used another computer program to search for complementary DNA segments.
They found that the microRNA matched up with parts of two genes called TGF-beta and SMAD3. These genes were already known to control cell suicide. The LAT microRNA silenced the effects of these two genes, Fraser’s team reports in the July 6 Nature.
“This is an exciting study that … provides a plausible mechanism for [herpes] latency,” says microRNA researcher Victor R. Ambros of Dartmouth Medical School in Hanover, N.H. He adds that the newly identified LAT microRNA might have evolved to take advantage of some normal, but currently unknown cellular process directed by microRNA.
Further information about how the LAT microRNA operates in cells could direct scientists as they craft herpes-fighting drugs, says Fraser. “This could be the first chink into the armor of the virus,” he adds.