Human herpesvirus 7 induces the functional up-regulation of tumor necrosisfactor-related apoptosis-inducing ligand (TRAIL) coupled to TRAIL-R1 down-modulation in CD4(+) T cells

Human herpesvirus 7 (HHV-7) is endemic in the adult human population. Altho ugh HHV-7 preferentially infects activated CD4(+) T lymphocytes, the conseq uence of T-cell infection for viral pathogenesis and immunity are still lar gely unknown. HHV-7 infection induces apoptosis mostly in uninfected bystan der cells but not in productively infected CD4(+) T cells. To dissect the u nderlying molecular events, the role of death-inducing ligands belonging to the tumor necrosis factor (TNF) cytokine superfamily was investigated. HHV -7 selectively up-regulated the expression of TNF-related apoptosis-inducin g ligand (TRAIL), but not that of CD95 ligand or TNF-alpha in lymphoblastoi d (SupT1) or primary activated CD4(+) T cells. Moreover, in a cell-to-cell- contact assay, HHV-7-infected CD4(+) T lymphocytes were cytotoxic for bysta nder uninfected CD4(+) T cells through the TRAIL pathway. By contrast, HHV- 7 infection caused a marked decrease of surface TRAIL-R1, but not of TRAIL- R2, CD95, TNF-R1, or TNF-R2. Of note, the down-regulation of TRAIL-R1 selec tively occurred in cells coexpressing HHV-7 antigens that became resistant to TRAIL-mediated cytotoxicity. These findings suggest that the TRAIL-media ted induction of T-cell death may represent an important immune evasion mec hanism of HHV-7, helping the virus to persist in the host organism througho ut its lifetime. (Blood. 2001;98;2474-2481) (C) 2001 by The American Societ y of Hematology.