Human herpesvirus 7 induces the functional up-regulation of tumor necrosis factor-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. Although HHV-7 preferentially infects activated CD4(+) T lymphocytes, the consequence of T-cell infection for viral pathogenesis and immunity are still largely unknown. HHV-7 infection induces apoptosis mostly in uninfected bystander cells but not in productively infected CD4(+) T cells. To dissect the underlying 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-inducing ligand (TRAIL), but not that of CD95 ligand or TNF-alpha in lymphoblastoid (SupT1) or primary activated CD4(+) T cells. Moreover, in a cell-to-cell-contact assay, HHV-7-infected CD4(+) T lymphocytes were cytotoxic for bystander 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 selectively occurred in cells coexpressing HHV-7 antigens that became resistant to TRAIL-mediated cytotoxicity. These findings suggest that the TRAIL-mediated induction of T-cell death may represent an important immune evasion mechanism of HHV-7, helping the virus to persist in the host organism throughout its lifetime.
Secchiero
P
P
Department of Morphology and Embryology, Human Anatomy Section, University of Ferrara, Italy.
Mirandola
P
P
Zella
D
D
Celeghini
C
C
Gonelli
A
A
Vitale
M
M
Capitani
S
S
Zauli
G
G
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D015704:CD4 Antigens / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D005786:Gene Expression Regulation; D016199:Herpesvirus 7, Human / Q000276:immunology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*; D019014:fas Receptor / Q000276:immunology
D051017:Apoptosis Regulatory Proteins; D015704:CD4 Antigens; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor