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 Dvhs 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.
INTRODUCTIONDendritic cells (DCs) are bone marrow-derived leukocytes and represent the best-known group of antigen-presenting cells (APCs) today. In order to induce specific T cellmediated immune responses, they act as the sentinels of the immune system and lie in wait in an immature state in almost all peripheral tissues (Banchereau & Steinman, 1998). Maturation is induced by contact of immature DCs with various products of infectious agents (Aliprantis et al., 1999;Brightbill et al., 1999;Cella et al., 1999). During maturation, DCs lose their ability to take up antigens and migrate from the sites of antigen accumulation to the areas of antigen presentation, primarily the T-cell zones of the secondary lymphoid organs (Banchereau & Steinman, 1998;Ridge et al., 1998).Immature DCs differ significantly from mature DCs in their response to specific chemokines, their ability to migrate and their capacity to stimulate immune responses (Gunn, 2003). Whilst immature DCs respond to many CC and CXC chemokines, such as CCL3 (MIP-1a), CCL4 (MIP-1b), CCL5 (RANTES) and CCL20 (MIP-3a), the expression or activity of the corresponding receptors is reduced or abolished completely in mature DCs 1998). As a consequence of the enhanced expression of CCR7 and CXCR4, mature DCs show an increased response to CCL19 (MIP-3b) and CXCL12 (SDF-1a) (Cavanagh & Von Andrian, 2002; Delgado et al., 1998; Förster et al., 1999;Gunn et al., 1999). The necessity of CCR7 expression for the induction of a primary immune response (Förster et al., 1999;Parlato et al., 2001) has ...