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Journal of Virology, September 2008, p. 9065-9074, Vol. 82, No. 18
0022-538X/08/$08.00+0     doi:10.1128/JVI.00961-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Human Cytomegalovirus Infection Alters the Expression of Cellular MicroRNA Species That Affect Its Replication

Fu-Zhang Wang,^1, Frank Weber,² Carlo Croce,³ Chang-Gong Liu,³ Xudong Liao,⁴ and Philip E. Pellett^1,5*

Departments of Molecular Genetics,¹ Molecular Cardiology,⁴ Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195,² Human Cancer Genetics Program, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210,³ Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, Michigan 48201⁵

Received 8 May 2008/ Accepted 24 June 2008

The human genome encodes over 500 microRNAs (miRNAs), small RNAs (19 to 26 nucleotides [nt]) that regulate the expressions of diverse cellular genes. Many cellular processes are altered through a variety of mechanisms by human cytomegalovirus (HCMV) infection. We asked whether HCMV infection leads to changes in the expression of cellular miRNAs and whether HCMV-regulated miRNAs are important for HCMV replication. Levels of most miRNAs did not change markedly during infection, but some were positively or negatively regulated. Patterns of miRNA expression were linked to the time course of infection. Some similarly reregulated miRNAs share identical or similar seed sequences, suggesting coordinated regulation of miRNA species that have shared targets. miRNAs miR-100 and miR-101 were chosen for further analyses based on their reproducible changes in expression after infection and on the basis of having predicted targets in the 3' untranslated regions (3'-UTR) of genes encoding components of the mammalian target of rapamycin (mTOR) pathway, which is important during HCMV infection. Reporter genes that contain the 3'-UTR of mTOR (predicted targets for miR-100 and miR-101) or raptor (a component of the mTOR pathway; predicted site for miR-100) were constructed. Mimics of miR-100 and miR-101 inhibited expression from the mTOR construct, while only miR-100 inhibited the raptor construct. Together, miR-100 and miR-101 reduced mTOR protein levels. While the miR-100 and miR-101 mimics individually modestly inhibited production of infectious progeny, much greater inhibition was achieved with a combination of both (33-fold). Our key finding is that HCMV selectively manipulates the expression of some cellular miRNAs to help its own replication.

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* Corresponding author. Mailing address: Department of Immunology and Microbiology, Wayne State University School of Medicine, 540 East Canfield Avenue, 6225 Scott Hall, Detroit, MI 48201. Phone: (313) 577-6494. Fax: (313) 577-1155. E-mail: ppellett{at}med.wayne.edu

Published ahead of print on 2 July 2008.

Present address: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.

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Journal of Virology, September 2008, p. 9065-9074, Vol. 82, No. 18
0022-538X/08/$08.00+0     doi:10.1128/JVI.00961-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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