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How miRNA hides cold sores The cold sore virus HSV-1 (herpes simplex virus 1) is notorious for its ability to lie dormant for months or years, allowing it to maintain life-long latent infections. The viral gene LAT, is known to be a key factor in inducing dormancy and now its non-coding RNA product has been identified as a precursor to four microRNAs (miRNAs), one of which appears to switch off viral gene expression in latently infected neurons. A second miRNA, not coded by LAT but with similar activity was also discovered. This raises the possibility that drugs based on blocking these miRNAs could in theory 'wake up, the virus, making them vulnerable to antiviral therapy. Herpes viruses maintain life-long latent infection. This paper provides evidence suggesting that latency is in part mediated by micro RNAs derived from the viral LAT gene, which are thought to downregulate key viral immediate early proteins. Herpesviruses are characterized by their ability to maintain life-long latent infections in their animal hosts. However, the mechanisms that allow establishment and maintenance of the latent state remain poorly understood. Herpes simplex virus 1 (HSV-1) establishes latency in neurons of sensory ganglia, where the only abundant viral gene product is a non-coding RNA, the latency associated transcript ( LAT ) 1 , 2 . Here we show that LAT functions as a primary microRNA (miRNA) precursor that encodes four distinct miRNAs in HSV-1 infected cells. One of these miRNAs, miR-H2-3p, is transcribed in an antisense orientation to ICP0 —a viral immediate-early transcriptional activator that is important for productive HSV-1 replication and thought to have a role in reactivation from latency 3 . We show that miR-H2-3p is able to reduce ICP0 protein expression, but does not significantly affect ICP0 messenger RNA levels. We also identified a fifth HSV-1 miRNA in latently infected trigeminal ganglia, miR-H6, which derives from a previously unknown transcript distinct from LAT . miR-H6 shows extended seed complementarity to the mRNA encoding a second HSV-1 transcription factor, ICP4, and inhibits expression of ICP4, which is required for expression of most HSV-1 genes during productive infection 4 . These results may explain the reported ability of LAT to promote latency 5 , 6 , 7 , 8 , 9 . Thus, HSV-1 expresses at least two primary miRNA precursors in latently infected neurons that may facilitate the establishment and maintenance of viral latency by post-transcriptionally regulating viral gene expression.

The microRNA (miRNA) and RNA interference (RNAi) pathways have recently emerged as an important aspect of virus-host cell interaction. This interaction can occur in several different ways and may favor either the virus or the host cell. Plants and invertebrates use RNAi as a first line of defense against virus infection by cleaving long, double-stranded viral transcripts into small interfering RNAs. However, it remains to be determined whether mammalian cells also initiate a similar response to infection. Here we present evidence that mammalian cells in fact do not induce an antiviral RNAi defense in response to infection by primate retroviruses. Viruses may also interact with host cells by encoding miRNAs to regulate either cellular or viral gene expression. Here we demonstrate that herpes simplex virus type 1 (HSV-1) encodes at least five miRNAs which are primarily expressed during latency. Two of these miRNAs modulate expression of viral genes required for productive replication. We hypothesize that down regulation of these viral genes by these latency associated miRNAs allows HSV-1 to establish and maintain the latent state.