Suppression of immediate-early viral gene expression by herpesvirus-coded microRNAs: Implications for latency

doi:10.1073/pnas.0711910105

Suppression of immediate-early viral gene expression by herpesvirus-coded microRNAs: Implications for latency

^†Simons Center for Systems Biology, Institute for Advanced Study, Princeton, NJ 08540;
*Department of Molecular Biology, Princeton University, Princeton, NJ 08544;
^‡Laboratory of Theoretical Physical Chemistry, Ecole Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland; and
^§Fred Hutchinson Cancer Research Center, Seattle, WA 98109

Contributed by Arnold J. Levine, December 19, 2007 (received for review November 20, 2007)

Abstract

A quantitative algorithm was developed and applied to predict target genes of microRNAs encoded by herpesviruses. Although there is almost no conservation among microRNAs of different herpesvirus subfamilies, a common pattern of regulation emerged. The algorithm predicts that herpes simplex virus 1, human cytomegalovirus, Epstein–Barr virus, and Kaposi's sarcoma-associated herpesvirus all employ microRNAs to suppress expression of their own genes, including their immediate-early genes. In the case of human cytomegalovirus, a virus-coded microRNA, miR-112-1, was predicted to target the viral immediate-early protein 1 mRNA. To test this prediction, mutant viruses were generated that were unable to express the microRNA, or encoded an immediate-early 1 mRNA lacking its target site. Analysis of RNA and protein within infected cells demonstrated that miR-UL112-1 inhibits expression of the major immediate-early protein. We propose that herpesviruses use microRNA-mediated suppression of immediate-early genes as part of their strategy to enter and maintain latency.

Footnotes

^¶To whom correspondence should be addressed. E-mail: alevine{at}ias.edu
Author contributions: E.M. and J.V. contributed equally to this work; E.M., J.V., T.S., and A.J.L. designed research; E.M. and J.V. performed research; H.R. contributed new reagents/analytic tools; E.M., J.V., T.S., and A.J.L. analyzed data; and E.M., J.V., T.S., and A.J.L. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0711910105/DC1.
Freely available online through the PNAS open access option.