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Journal of Virology, July 2004, p. 7536-7544, Vol. 78, No. 14
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.14.7536-7544.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Gain of Virulence Caused by Loss of a Gene in Murine Cytomegalovirus{ddagger}

Ivan Bubic,1,{dagger} Markus Wagner,2,§ Astrid Krmpotic,1 Tanja Saulig,1 Sungjin Kim,3 Wayne M. Yokoyama,3 Stipan Jonjic,1* and Ulrich H. Koszinowski2

Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia,1 Max von Pettenkofer Institute, LMU, D-80336 Munich, Germany,2 Howard Hughes Medical Institute, Rheumatology Division, Washington University School of Medicine, St. Louis, Missouri 631103

Received 10 November 2003/ Accepted 12 March 2004

Mouse strains are either resistant or susceptible to murine cytomegalovirus (MCMV). Resistance is determined by the Cmv1r (Ly49h) gene, which encodes the Ly49H NK cell activation receptor. The protein encoded by the m157 gene of MCMV has been defined as a ligand for Ly49H. To find out whether the m157 protein is the only Ly49H ligand encoded by MCMV, we constructed the m157 deletion mutant and a revertant virus. Viruses were tested for susceptibility to NK cell control in Ly49H+ and Ly49H– mouse strains. Deletion of the m157 gene abolished the viral activation of Ly49H+ NK cells, resulting in higher virus virulence in vivo. Thus, in the absence of m157, Ly49H+ mice react like susceptible strains. 129/SvJ mice lack the Ly49H activation NK cell receptor but express the inhibitory Ly49I NK cell receptor that binds to the m157 protein. The {Delta}m157 inhibitory phenotype was weak because MCMV encodes a number of proteins that mediate NK inhibition, whose contribution could be shown by another mutant.

* Corresponding author. Mailing address: Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, B. Branchetta 20, 51000 Rijeka, Croatia. Phone: 385 51 651 206 or 170. Fax: 385 51 651 176. E-mail: jstipan{at}medri.hr.

{ddagger} Supplemental material for this article may be found at http://jvi.asm.org/.

{dagger} Ivan Bubi and Markus Wagner contributed equally to this work.

§ Present address: Department of Pathology, Harvard Medical School, Boston, MA 02115.

Journal of Virology, July 2004, p. 7536-7544, Vol. 78, No. 14
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.14.7536-7544.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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