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Science 317 (5836): 376-381

Copyright © 2007 by the American Association for the Advancement of Science

Host Immune System Gene Targeting by a Viral miRNA

Noam Stern-Ginossar,1* Naama Elefant,2* Albert Zimmermann,3 Dana G. Wolf,4 Nivin Saleh,4 Moshe Biton,1 Elad Horwitz,1 Zafnat Prokocimer,1 Mark Prichard,5 Gabriele Hahn,6{dagger} Debra Goldman-Wohl,7 Caryn Greenfield,7 Simcha Yagel,7 Hartmut Hengel,3 Yael Altuvia,2{ddagger} Hanah Margalit,2*{ddagger} Ofer Mandelboim1*{ddagger}

Abstract: Virally encoded microRNAs (miRNAs) have recently been discovered in herpesviruses. However, their biological roles are mostly unknown. We developed an algorithm for the prediction of miRNA targets and applied it to human cytomegalovirus miRNAs, resulting in the identification of the major histocompatibility complex class I–related chain B (MICB) gene as a top candidate target of hcmv-miR-UL112. MICB is a stress-induced ligand of the natural killer (NK) cell activating receptor NKG2D and is critical for the NK cell killing of virus-infected cells and tumor cells. We show that hcmv-miR-UL112 specifically down-regulates MICB expression during viral infection, leading to decreased binding of NKG2D and reduced killing by NK cells. Our results reveal a miRNA-based immunoevasion mechanism that appears to be exploited by human cytomegalovirus.

1 Lautenberg Center for General and Tumor Immunology, Hebrew University Hadassah Medical School, Jerusalem, Israel.
2 Department of Molecular Genetics and Biotechnology, Hebrew University Hadassah Medical School, Jerusalem, Israel.
3 Institute for Virology, Heinrich Heine University, D40225 Düsseldorf, Germany.
4 Department of Clinical Microbiology and Infectious Diseases, Hadassah University Hospital, Jerusalem, Israel.
5 Department of Pediatrics, University of Alabama, Birmingham, AL 35233, USA
6 Max von Pettenkofer Institut, Department of Virology, D80336 Munich, Germany.
7 Department of Obstetrics and Gynecology, Hadassah Hebrew University Hospital Mount Scopus, Jerusalem, Israel.

* These authors contributed equally to this work.

{dagger} Present address: Klinikum Ingolstadt, Institut für Laboratoriumsmedizin, D84049 Ingolstadt, Germany.

{ddagger} To whom correspondence should be addressed. E-mail: yaelal{at}md.huji.ac.il (Y.A.); hanahm{at}ekmd.huji.ac.il (H.M.); oferm{at}ekmd.huji.ac.il (O.M.)

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