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

Nature volume 454, pages 780–783 (2008)Cite this article

Abstract

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 latency3. 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 infection4. These results may explain the reported ability of LAT to promote latency5,6,7,8,9. 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.

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Figure 1: Genomic location of HSV-1 miRNAs.
Figure 2: HSV-1 pre-miRNAs.
Figure 3: Downregulation of ICP0 protein expression by HSV-1 miR-H2-3p.
Figure 4: Downregulation of ICP4 protein expression by HSV-1 miR-H6.

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Acknowledgements

We thank R. Sandri-Goldin for reagents used in this research and S. Boissel for contributions to PCR primer design. This work was supported by National Institutes of Health grants to B.R.C. and D.M.C.

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Authors and Affiliations

  1. Department of Molecular Genetics and Microbiology and Center for Virology, Duke University Medical Center, Durham, North Caroline 27710, USA,

    Jennifer Lin Umbach, Heather W. Karnowski & Bryan R. Cullen

  2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA,

    Martha F. Kramer, Igor Jurak & Donald M. Coen

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  1. Jennifer Lin Umbach
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Correspondence to Bryan R. Cullen.

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Supplementary Information

The file contains Supplementary Figures 1-3 with Legends and Supplementary Tables 1-6 and Legends. The figures show control data and additional experimental data in support of the manuscript’s conclusions. (PDF 631 kb)

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Umbach, J., Kramer, M., Jurak, I. et al. MicroRNAs expressed by herpes simplex virus 1 during latent infection regulate viral mRNAs. Nature 454, 780–783 (2008). https://doi.org/10.1038/nature07103

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