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

Nature. 2008 Aug 7;454(7205):780-3. doi: 10.1038/nature07103. Epub 2008 Jul 2.


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). 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. 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. These results may explain the reported ability of LAT to promote latency. 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Base Sequence
  • Cell Line
  • Down-Regulation
  • Gene Expression Regulation, Viral*
  • Genome, Viral / genetics
  • Herpesvirus 1, Human / genetics*
  • Herpesvirus 1, Human / physiology
  • Humans
  • Immediate-Early Proteins / biosynthesis
  • Immediate-Early Proteins / genetics
  • Male
  • Mice
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism*
  • RNA Processing, Post-Transcriptional
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Viral / genetics*
  • RNA, Viral / metabolism*
  • Ubiquitin-Protein Ligases / biosynthesis
  • Ubiquitin-Protein Ligases / genetics
  • Virus Latency / genetics*
  • Virus Latency / physiology


  • Immediate-Early Proteins
  • MicroRNAs
  • RNA, Messenger
  • RNA, Viral
  • herpes simplex virus, type 1 protein ICP4
  • latency associated transcript, herpes simplex virus-1
  • Ubiquitin-Protein Ligases
  • Vmw110 protein, Human herpesvirus 1