Inhibition of human herpes simplex virus type 2 by interferon gamma and tumor necrosis factor alpha is mediated by indoleamine 2,3-dioxygenase.
Genital herpes simplex virus type 2 (HSV-2) is a significant clinical problem. Infection in pregnancy may result in disseminated infection of the newborn with encephalitis. We analyzed the antiviral effects induced by interferon-gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) in cervix carcinoma cells (HeLa) and astrocytoma cells (86HG39). We found that replication of HSV-2 in HeLa cells and in 86HG39 cells is inhibited after stimulation of the cells by IFN-gamma and TNF-alpha. The antiviral effect of IFN-gamma is enhanced in the presence of TNF-alpha, while stimulation by TNF-alpha alone did not induce antiviral activity. We found that IFN-gamma induces a strong activation of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) and in addition, that the IFN-gamma-induced IDO activity was enhanced in the presence of TNF-alpha. Furthermore, we found that the induction of IDO activity is responsible for the inhibition of herpes simplex virus replication, since the presence of excess amounts of l-tryptophan abrogates the antiviral effect induced by IFN-gamma and the combination of IFN-gamma and TNF-alpha. We therefore conclude that the antiviral effect against HSV-2 mediated by type II interferon and TNF-alpha are dependent on IDO activation.
Adams
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O
Institut für Virologie, Heinrich-Heine-Universität, Universitätsstrasse 1, D-40225 Düsseldorf, Germany.
Besken
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K
Oberdörfer
C
C
MacKenzie
C R
CR
Rüssing
D
D
Däubener
W
W
D000998:Antiviral Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D006367:HeLa Cells; D018258:Herpesvirus 2, Human / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma / Q000494:pharmacology*; D011994:Recombinant Proteins; D014364:Tryptophan / Q000378:metabolism; D014366:Tryptophan Oxygenase / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D014364:Tryptophan; D014366:Tryptophan Oxygenase