Frontline: Induction of apoptosis and modulation of c‐FLIPL and p53 in immature dendritic cells infected with herpes simplex virus

Herpes simplex virus (HSV) can perturb the function of dendritic cells (DC). The underlying mechanisms are not defined. In the present study we demonstrate that HSV induces a substantial number of immature DC to undergo apoptosis by a mechanism involving caspase‐8. We found strongly enhanced expression of TNF‐α and TRAIL but not CD95 ligand after HSV infection. Blocking experiments suggested that these classical death ligands contribute to HSV‐induced cell death of immature DC. Because uninfected DC are resistant to the apoptosis‐inducing effect of death ligands we searched fora viral "competence‐to‐die" signal. Further analysis revealed that HSV‐infected immature DC down‐regulate long cellular FLICE‐inhibitory protein (c‐FLIPL) and up‐regulate p53 whereas otherapoptosis‐regulating proteins (e.g. Bcl‐2, RIP, FADD) were not affected. Down‐regulation of c‐FLIPL was not due to diminished gene transcription or reduced mRNA stability because the level of c‐FLIPL mRNA was rather increased. Moreover, down‐regulation of c–FLIPL could not be blocked by the anti‐herpetic drug acyclovir. Finally, the underlying mechanism was also operative in human umbilical vein endothelial cells, which show a similar susceptibility to HSV infection and strength of c‐FLIPL expression. These results suggest that HSV targets c‐FLIPL protein in immature DC and other infectable cells to disrupt their function.