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Published online before print November 2, 2004

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0504301

Received for publication May 21, 2004.
Revised September 4, 2004.
Accepted for publication October 6, 2004.

Article

Human cytomegalovirus inhibits the migration of immature dendritic cells by down-regulating cell-surface CCR1 and CCR5

Stefania Varani ^*, Giada Frascaroli , Mohammed Homman-Loudiyi ^*, Sari Feld ^*, Maria Paola Landini , and Cecilia Söderberg-Nauclér ^*@

*Department of Medicine, Karolinska Systems Biomedicine Center, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Clinical and Experimental Medicine, University of Bologna, Italy; and Abteilung Virologie, Universitätsklinikum Ulm, Germany

^@ To whom correspondence should be addressed. E-mail: cecilia.soderberg.naucler{at}cmm.ki.se.

	Abstract

Dendritic cells (DC) play a key role in the host immune response to infections. Human cytomegalovirus (HCMV) infection can inhibit the maturation of DC and impair their ability to stimulate T cell proliferation and cytotoxicity. In this study, we assessed the effects of HCMV infection on the migratory behavior of human DC. The HCMV strain TB40/E inhibited the migration of immature monocyte-derived DC in response to inflammatory chemokines by 95% 1 day after infection. This inhibition was mediated by early viral replicative events, which significantly reduced the cell-surface expression of CC chemokine receptor 1 (CCR1) and CCR5 by receptor internalization. CMV infection also induced secretion of the inflammatory chemokines CC chemokine ligand 3 (CCL3)/macrophage inflammatory protein-1 (MIP-1), CCL4/MIP-1, and CCL5/regulated on activation, normal T expressed and secreted. Neutralizing antibodies for these chemokines reduced the effects of HCMV on chemokine receptor expression and on DC migration by 60%. It is interesting that the surface expression of the lymphoid CCR7 was not up-regulated after HCMV infection on immature DC, and immature-infected DC did not migrate in response to CCL19/MIP-3. These findings suggest that blocking the migratory ability of DC may be a potent mechanism used by HCMV to paralyze the early immune response of the host.

Key Words: viral infection • antigen-presenting cells • chemotaxis • chemokines

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