Abstract
Abstract: :
Purpose: Herpes simplex virus type 1 (HSV-1) initially infects mucosal tissues such as the eye where it replicates prior to traveling up nerves and establishing a latent infection. The strategic positioning of immature dendritic cells (DC) in mucosal tissues makes them likely to be the primary HSV-1 antigen-presenting cells (APC). Immature DC expressing viral antigens must be activated to mature, before they can serve as APC. HSV-1 can infect DC and interfere with their maturation. The stimuli and the viral genes involved in this interference remain to be determined. Our goal was to investigate the role of the HSV-1 Latency Associated Transcript (LAT), the only viral gene abundantly transcribed during both acute and latent infection, on DC maturation and function. Methods: Murine bone marrow derived DC were infected in vitro with i) the LAT null mutant dLAT2903; ii) its marker rescued virus dLAT2903R or iii) the parental HSV-1 strain McKrae. The levels of expression of CD40, CD54, CD80, CD86 and MHC class I and class II molecules were measured by flow cytometry. These membrane molecules are all indicators of DC maturation. The presence of viral antigens on CD11c positive cells was also determined. Results: DC infected with dLAT2903 virus expressed the highest level of viral proteins compared to DC infected with dLAT2903R or McKrae. In contrast, in CV-1 cells and RS cells, the level of viral proteins was similar with all viruses. Infection of immature DC with dLAT2903, but not with McKrae or dLAT2903R, led to significant, selective, and asynchronous down-regulation of CD40, CD54, CD80, CD86, and MHC class I molecules. Differences were also observed in T cell stimulation induced by dLAT2903 compared to dLAT2903R and McKrae infected DC. Conclusion: i) In DC cells, LAT inhibited cell surface expression of viral antigens, which may delay T cell activation, allowing more time for replication of HSV-1. ii) LAT appeared to either directly or indirectly enhance DC maturation. iii) These results may help to elucidate the mechanism of action of LAT on DC and highlight a new mechanism used by HSV-1 to evade the immune system.
Keywords: 425 herpes simplex virus • 380 cytokines/chemokines • 435 immunomodulation/immunoregulation