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MicroRNAs Key to Cold Sore Virus Latency, Research Shows

NEW YORK (GenomeWeb News) – New research is revealing the strategy that cold sore viruses use to remain dormant in the bodies of their hosts — and providing clues about how to drive the virus out of this dormancy and into a treatable state.
 
Researchers from Duke and Harvard Universities used pyrosequencing to identify a handful of microRNAs that are produced when cold sore viruses are in a latent stage of infection. They also discovered a transcription factor and a transcription activator that are silenced by two of the miRNAs. The work, published online today in Nature, is expected to facilitate the development of better cold sore treatments and, perhaps, provide insights into treating other viruses as well.
 
Cold sores, recurring blister-like sores around the mouth, are caused by a virus called the herpes simplex virus 1. Bouts of cold sores occur intermittently in those who carry the virus, always in the same place. Between these outbreaks, HSV-1 can remain dormant for years, lingering in the trigeminal nerve, which innervates the face. Although active HSV1 virus can be destroyed using antiviral drugs such as acyclovir, dormant viruses evade this treatment.
 
“Inactive virus is completely untouchable by any treatment we have,” senior author Bryan Cullen, director of Duke University’s Center for Virology, said in a statement. “Unless you activate the virus, you can’t kill it.”
 
To activate the virus, though, scientists need to understand what keeps it dormant — and that has remained tricky. Scientists knew that HSV-1 produces a non-coding RNA called LAT RNA during dormancy, but weren’t sure what that RNA did.
 
“It was very mysterious because it was a non-coding RNA and also an unstable RNA,” Cullen told GenomeWeb Daily News today.
 
Although others have predicted that herpes viruses used miRNAs to achieve and maintain latency, many questions remained about the players in this potential regulation.
 
In an effort to understand LAT’s function, Cullen and his co-workers expressed the RNA in human 293T cells, isolated it, and sequenced complementary DNA using 454 sequencing. They discovered that LAT RNA is actually a miRNA precursor that gets processed into four different miRNAs. One of these, miR-H2-3p, appears to silence a transcriptional activator called ICP0.
 
They then looked at whether that was true in vivo by isolating small miRNAs from the trigeminal nerve of HSV-1 infected mice and doing deep sequencing on cDNAs.
 
Again, they detected the miRNAs produced from LAT RNA. But they also found another miRNA called miR-H6 that’s believed to bind and silence a transcription factor called ICP4. ICP4, in turn, seems to control the expression of most HSV-1 genes during the virus’ active state, and turns on most HSV-1 genes.
 
“That was a big surprise,” Cullen said, because it means there has to be at least one miRNA precursor other than LAT that is expressed during latency. Based on these findings, the researchers concluded that, during dormancy, HSV-1 uses at least two miRNA precursors to generate miRNAs that establish and maintain viral latency.
 
“Obviously when you have more mRNA than miRNAs that’s not going to work,” he said. When the virus becomes active, it seems to ramp up the expression of ICP0 and ICP4 until they titrate out the available miRNA, Cullen explained, and the other viral genes are expressed.
 
Next, Cullen and his colleagues plan to characterize the new miRNAs to get an even better handle on what they are doing during latency. Eventually, the team hopes to exploit these findings to develop drugs that drive HSV-1 into an active — and treatable — state. For instance, it may be possible to block miRNA function using antisense reagents, which should theoretically push all of a host’s viruses into an active state that is sensitive to antivirals.
 
Cullen said he and co-author Donald Coen, a molecular pharmacologist at Harvard Medical School, are currently conducting mouse experiments aimed at doing just that. Although he noted that finding an appropriate drug delivery system is the most difficult aspect of using antisense reagents, Cullen expressed enthusiasm about the promise of such an approach.
 
“I think we’ll see more and more of this kind of thing coming down the pike,” he said.
 
And, Cullen added, if it works for HSV-1 the miRNA-blocking approach may also provide insights into treating other latent viruses, such as the virus that causes chicken pox in children and shingles in older adults and the herpes simplex 2 virus, which causes genital herpes.
 

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