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

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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. HCMV infection also induced secretion of the inflammatory chemokines CC chemokine ligand 3 (CCL3)/macrophage inflammatory protein-1α (MIP-1α), CCL4/MIP-1β, and CCL5/regulated on activation, normal T expressed and secreted (RANTES). Neutralizing antibodies for these chemokines reduced the effects of HCMV on chemokine receptor expression and on DC migration by ∼60%. Interestingly, the surface expression of the lymphoid chemokine receptor CCR7 was not up-regulated after HCMV infection on immature DC, and immature-infected DC did not migrate in response to CCL19/MIP-3β. 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.
Funding Information
  • Swedish Research Council (K2004-16X-12615-07A)
  • Swedish Society of Medicine (2003-633)
  • Tobias Foundation (33/02, 28/03)
  • Swedish Children Cancer Research Foundation (PROJ01/046)
  • Emil and Wera Cornells Foundation
  • Heart and Lung Foundation (20010486, 20030830)

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