Infection of mature dendritic cells with herpes simplex virus type 1 dramatically reduces lymphoid chemokine-mediated migration.
Herpes simplex virus type 1 (HSV-1) is able to establish latency in infected individuals. In order to characterize potential new immune-escape mechanisms, mature dendritic cells (DCs) were infected with HSV-1 and total cellular RNA was isolated from infected and mock-infected populations at different time points. RNA profiling on Affymetrix Human Genome U133A arrays demonstrated a dramatic downregulation of the migration-mediating surface molecules CCR7 and CXCR4, an observation that was further confirmed by RT-PCR and fluorescence-activated cell sorting analyses. Furthermore, migration assays revealed that, upon infection of mature DCs, CCR7- and CXCR4-mediated migration towards the corresponding CCL19 and CXCL12 chemokine gradients was strongly reduced. It is noteworthy that the infection of immature DCs with HSV-1 prior to maturation led to a failure of CCR7 and CXCR4 upregulation during DC maturation and, as a consequence, also induced a block in their migratory capacity. Additional migration assays with a Deltavhs mutant virus lacking the virion host shutoff (vhs) gene, which is known to degrade cellular mRNAs, suggested a vhs-independent mechanism. These results indicate that HSV-1-infected mature DCs are limited in their capacity to migrate to secondary lymphoid organs, the areas of antigen presentation and T-cell stimulation, thus inhibiting an antiviral immune response. This represents a novel, previously unrecognized mechanism for HSV-1 to escape the human immune system.
Prechtel
Alexander T
AT
Department of Dermatology, University Hospital Erlangen, Hartmannstrasse 14, D-91052 Erlangen, Germany.
Turza
Nadine M
NM
Department of Dermatology, University Hospital Erlangen, Hartmannstrasse 14, D-91052 Erlangen, Germany.
Kobelt
Dieter J
DJ
Department of Dermatology, University Hospital Erlangen, Hartmannstrasse 14, D-91052 Erlangen, Germany.
Eisemann
Jutta I
JI
Department of Dermatology, University Hospital Erlangen, Hartmannstrasse 14, D-91052 Erlangen, Germany.
Coffin
Robert S
RS
BioVex Ltd, Oxford OX14 4RX, UK.|Department of Immunology and Molecular Pathology, University College London, London W1P 6DB, UK.
McGrath
Yvonne
Y
BioVex Ltd, Oxford OX14 4RX, UK.
Hacker
Christine
C
Max Delbruck Center for Molecular Medicine, MDC, Robert-Rossle-Str. 10, 13092 Berlin, Germany.
Ju
Xinsheng
X
Institute for Biomedical Technology, Department of Cell Biology, University Hospital Aachen, Aachen, Germany.|Max Delbruck Center for Molecular Medicine, MDC, Robert-Rossle-Str. 10, 13092 Berlin, Germany.
Zenke
Martin
M
Institute for Biomedical Technology, Department of Cell Biology, University Hospital Aachen, Aachen, Germany.|Max Delbruck Center for Molecular Medicine, MDC, Robert-Rossle-Str. 10, 13092 Berlin, Germany.
Steinkasserer
Alexander
A
Department of Dermatology, University Hospital Erlangen, Hartmannstrasse 14, D-91052 Erlangen, Germany.
D002454:Cell Differentiation; D002465:Cell Movement; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D015536:Down-Regulation; D006561:Herpes Simplex / Q000276:immunology; D018259:Herpesvirus 1, Human / Q000276:immunology*; D006801:Humans; D009154:Mutation; D012333:RNA, Messenger / Q000032:analysis; D054400:Receptors, CCR7; D019718:Receptors, CXCR4 / Q000032:analysis / Q000235:genetics; D019707:Receptors, Chemokine / Q000032:analysis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012260:Ribonucleases; D013997:Time Factors; D014764:Viral Proteins / Q000235:genetics
C515370:CCR7 protein, human; D012333:RNA, Messenger; D054400:Receptors, CCR7; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D014764:Viral Proteins; C070722:virion host shutoff protein, Simplexvirus; D012260:Ribonucleases