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Study Finds Herpesviruses Use miRNA to Silence Genes During Latency

NEW YORK (GenomeWeb News) – New research suggest that microRNAs help viruses in the herpesvirus family hide out and remain dormant in the host body for months or even years between symptomatic infections.
American and Swiss researchers used a quantitative algorithm to predict viral miRNA sites of action based on their sequence. The algorithm predicted that a human cytomegalovirus miRNA called miR-UL112-1 binds to and regulates mRNA for genes suppressed during viral latency — a finding the team verified experimentally. The results, which appeared online today in the Proceedings of the National Academy of Sciences, also suggest that other herpeseviruses use similar mechanisms while seemingly dormant.
“[W]e propose that herpesviruses use a common miRNA-based strategy to maintain latency,” the authors wrote.
MicroRNAs are non-protein coding RNAs around 20 nucleotides long that bind messenger RNA and interfere with its translation, silencing the gene. Many herpesviruses seem to transcribe these miRNAs, even while latent.
The herpesviruses are a family of relatively large, double-stranded DNA viruses that infect vertebrates. Common examples include herpes simplex virus 1, human cytomegalovirus, Epstein-Barr virus, and Kaposi’s sarcoma-associated virus. These viruses remain latent or dormant for long stretches of time, during which there is only a small amount of viral replication.
The viruses resurface during a so-called lytic replication stage, causing infection. Lytic replication itself has three stages: an immediate-early stage, which prepares gene products used in infection; an early stage, involving viral DNA replication; and a late stage, during which the virus’ structural proteins are produced.
Senior author Arnold Levine, a researcher at the Simons Center for Systems Biology at the Institute for Advanced Study in Princeton, NJ, and his colleagues suspected that some herpesvirus miRNAs might inhibit viral genes, keeping viruses in a quiescent, latent state. To test this, his team developed a quantitative algorithm to predict just which genes the herpes virus miRNAs target.
“[O]ur algorithm uses a combination of analytical expressions and Monte Carlo simulations to determine exact probabilities that predicted miRNA targets would occur by chance,” the authors wrote.
When they used this algorithm to evaluate miRNAs in human cytomegalovirus, the researchers found that it predicted that an miRNA called miR-UL112-1 would bind the 3’ untranslated region of IE1 mRNA. IE1 is a major product of the HCMV intermediate-early transcriptional locus needed for efficient viral replication.
Indeed, when the researchers tested miR-UL112-1 experimentally, it did seem to bind to and regulate the IE1 UTR. For instance, they found that IE1 protein synthesis was significantly higher in viruses that were modified to lack miR-UL112-1 interactions with IE1 mRNA than it was in wild type viruses 48 hours after infection — even though there were no detectable differences in the IE1 mRNA levels.
Along with these immediate-early genes, the algorithm also predicts that herpesviruses contain miRNAs that target other viral functions such as replication, apoptosis, and host immune system evasion.
Similarly, in an article published last November in the journal PLoS Pathogens, senior author Jay Nelson, a microbiologist and virologist at the Oregon Health Sciences University, and his colleagues used comparative bioinformatics to show that miR-UL112-1 targeted three viral mRNAs, including the major immediate-early gene. They also suggest that the miRNA regulates genes involved in replication.
Though miRNAs are not conserved between different herpesvirus sub-families, the algorithm used in the latest research predicts that many herpesviruses encode miRNAs that suppress their own genes during early infection.  
“We propose that herpesviruses use microRNA-mediated suppression of immediate-early genes as part of their strategy to enter and maintain latency,” the authors wrote. “[I]f miRNAs are indeed central agents responsible for the maintenance of latency, this would explain the mysterious failure to detect proteins in the latent stage of [herpes simplex virus-1].”

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