1. Department of Molecular Genetics and Microbiology and Center for Virology, Duke University Medical Center, Durham, North Caroline 27710, USA
2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA

Correspondence to: Bryan R. Cullen¹ Correspondence and requests for materials should be addressed to B.R.C. (Email: culle002@mc.duke.edu).

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 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.

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