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Journal of Virology, April 2003, p. 4539-4545, Vol. 77, No. 8
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.8.4539-4545.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The Human Cytomegalovirus Protein UL16 Mediates Increased Resistance to Natural Killer Cell Cytotoxicity through Resistance to Cytolytic Proteins

Jenny Odeberg,1 Helena Browne,2 Sunil Metkar,3 Christopher J. Froelich,3 Lars Brandén,4 David Cosman,5 and Cecilia Söderberg-Nauclér1*

Department of Medicine, Center for Molecular Medicine,1 Clinical Research Center, Novum, Karolinska Institute, Stockholm, Sweden,4 Division of Virology, University of Cambridge, Cambridge, United Kingdom,2 Evanston Northwestern Healthcare Research Institute, Evanston, Illinois,3 Department of Immunobiology, Immunex Corporation, Seattle, Washington5

Received 3 October 2002/ Accepted 13 January 2003

Several reports have shown that human cytomegalovirus (HCMV)-infected cells are resistant to NK lysis. These studies have focused on receptor-ligand interactions, and different HCMV proteins have been indicated to mediate inhibitory NK signals. Here, we report that the HCMV protein UL16 is of major importance for the ability of HCMV-infected cells to resist NK cell-mediated cytotoxicity. Fibroblasts infected with the UL16 deletion mutant HCMV strain exhibited a 70% increased sensitivity to NK killing at 7 days postinfection compared to AD169-infected cells. Interestingly, HCMV-infected cells did not appear to engage inhibitory molecules on NK cells, since the levels of granzyme B were not reduced in supernatants obtained from NK cell cocultures with infected target cells compared to uninfected target cells. Furthermore, HCMV-infected cells, but not cells infected with the UL16 deletion mutant HCMV strain, exhibited a significantly increased resistance to the action of cytolytic proteins, including perforin, granzyme B, streptolysin O, and porcine NK lysin. In addition, fluorescence-activated cell sorting for UL16-positive transfected cells resulted in protection levels of 90% compared to control cells carrying the green fluorescent protein vector. Thus, the UL16 protein mediates an increased protection against the action of cytolytic proteins released by activated NK cells, possibly by a membrane-stabilizing mechanisms, rather than by delivering negative signals to NK cells.

* Corresponding author. Mailing address: Karolinska Institute, Department of Medicine, Center for Molecular Medicine, L8:03, Karolinska Hospital, S-171 76 Stockholm, Sweden. Phone: 46-8-517 798 96. Fax: 46-8-31 31 47. E-mail: cecilia.soderberg.naucler{at}cmm.ki.se.

Journal of Virology, April 2003, p. 4539-4545, Vol. 77, No. 8
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.8.4539-4545.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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