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Journal of Virology, May 2003, p. 5557-5570, Vol. 77, No. 10
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.10.5557-5570.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Role of Murine Cytomegalovirus US22 Gene Family Members in Replication in Macrophages

Carine Ménard,1 Markus Wagner,1 Zsolt Ruzsics,1 Karina Holak,1 Wolfram Brune,1,{dagger} Ann E. Campbell,2 and Ulrich H. Koszinowski1*

Department of Virology, Max von Pettenkofer Institute, Ludwig Maximilians University Munich, 80336 Munich, Germany,1 Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, Virginia 235072

Received 26 December 2002/ Accepted 10 February 2003

The large cytomegalovirus (CMV) US22 gene family, found in all betaherpesviruses, comprises 12 members in both human cytomegalovirus (HCMV) and murine cytomegalovirus (MCMV). Conserved sequence motifs suggested a common ancestry and related functions for these gene products. Two members of this family, m140 and m141, were recently shown to affect MCMV replication on macrophages. To test the role of all US22 members in cell tropism, we analyzed the growth properties in different cell types of MCMV mutants carrying transposon insertions in all 12 US22 gene family members. When necessary, additional targeted mutants with gene deletions, ATG deletions, and ectopic gene revertants were constructed. Mutants with disruption of genes M23, M24, m25.1, m25.2, and m128 (ie2) showed no obvious growth phenotype, whereas growth of M43 mutants was reduced in a number of cell lines. Genes m142 and m143 were shown to be essential for virus replication. Growth of mutants with insertions into genes M36, m139, m140, and m141 in macrophages was severely affected. The common phenotype of the m139, m140, and m141 mutants was explained by an interaction at the protein level. The M36-dependent macrophage growth phenotype could be explained by the antiapoptotic function of the gene that was required for growth on macrophages but not for growth on other cell types. Together, the comprehensive set of mutants of the US22 gene family suggests that individual family members have diverged through evolution to serve a variety of functions for the virus.

* Corresponding author. Mailing address: Max von Pettenkofer Institut, Pettenkoferstrasse 9a, D-80336 Munich, Germany. Phone: 4989 5160 5290. Fax: 4989 5160 5292. E-mail: koszinowski{at}m3401.mpk.med.uni-muenchen.de.

{dagger} Present address: Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, D-97078 Würzburg, Germany.

Journal of Virology, May 2003, p. 5557-5570, Vol. 77, No. 10
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.10.5557-5570.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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