Journal Article

MicroRNAs expressed by herpes simplex virus 1 during latent infection regulate viral mRNAs

Cullen, Bryan R., Karnowski, Heather W., Jurak, Igor, Umbach, Jennifer Lin, Coen, Donald M., Kramer, Martha F.

2008

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: Animals / Base Sequence / Biological and medical sciences / Cell Line / Down-Regulation / Gene expression / Gene Expression Regulation, Viral / Genetic aspects / Genome, Viral - genetics / Health aspects / Herpes / Herpes simplex virus / Herpes simplex virus 1 / Herpesvirus 1, Human - genetics / Herpesvirus 1, Human - physiology / Herpesvirus diseases / Human viral diseases / Humanities and Social Sciences / Humans / Immediate-Early Proteins - biosynthesis / Immediate-Early Proteins - genetics / Infectious diseases / letter / Male / Medical sciences / Messenger RNA / Mice / MicroRNAs - genetics / MicroRNAs - metabolism / multidisciplinary / Properties / RNA Processing, Post-Transcriptional / RNA, Messenger - genetics / RNA, Messenger - metabolism / RNA, Viral - genetics / RNA, Viral - metabolism / Science / Ubiquitin-Protein Ligases - biosynthesis / Ubiquitin-Protein Ligases - genetics / Viral diseases / Viral diseases with cutaneous or mucosal lesions and viral diseases of the eye / Virus Latency - genetics / Virus Latency - physiology