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

By J. L. Umbach, M. Kramer, I. Jurak, Heather W. Karnowski, D. Coen, Bryan R. Cullen. Nature, 2008

720 citations recorded by the source corpus.

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.

Subfields: Animal Science and Zoology, Epidemiology, Immunology

View Paper: https://www.semanticscholar.org/paper/84dc7d7399a80b420a9da506978518f32ee45866

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In Immunology

1. Olivier Voinnet
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Citations in the corpus

• MicroRNA Functions in Stress Responses (2010, positive): “For example, herpes simplex virus 1 expresses its own set of miRNAs that downregulate viral immediate-early proteins to lie dormant in the trigeminal nerve of the face (Umbach et al., 2008).”
• MicroRNA control in the immune system: basic principles. (2009, background): “miRNAs expressed by herpes simplex virus 1 (HSV-1) facilitate the establishment and maintenance of viral latency through a similar mechanism (Umbach et al., 2008).”
• Revisiting the principles of microRNA target recognition and mode of action (2009, background): “pl?acc=MI0008937">miR-H2-3p , which is produced by latent herpes simplex virus 1 in human cells, strongly represses the viral transcriptional activator ICP0 exclusively at the protein level, despite the existence of a perfectly complementary miR-H2-3p target site in the ICP0 mRN”