In vivo protective effect of tumour necrosis factor alpha against experimental infection with herpes simplex virus type 1.

C57BL/6 mice, which differ genetically from other strains by their resistance to herpes simplex virus type 1 (HSV-1) infection, were inoculated intraperitoneally with different doses of tumour necrosis factor alpha (TNF-alpha). Mice pretreated with 100 ng, or even 10 ng, of TNF-alpha showed prolonged survival compared to control mice that were infected with 10(7) p.f.u. of HSV-1. Significant protection was observed in mice injected 4 or 8 h prior to or after HSV-1 inoculation, respectively. Protection was also observed when mice which differed at their H-2 locus were treated with TNF-alpha after infection with HSV-1. Interferon could not be detected in the sera of mice at different time points after infection with HSV-1 or injection of TNF-alpha and there was no enhanced interferon titre in mice treated with both TNF-alpha and HSV-I, suggesting some interferon-independent protection. However, mice treated with TNF-alpha showed a marked activation of natural killer (NK) cells compared to untreated control mice or mice that were treated with HSV-1 alone. To test whether enhanced NK cell activity is responsible for TNF-alpha-induced protection, mice were injected with the NK cell-specific antibody anti-asialo Gm-1. In this experimental protocol the survival rate was almost unaffected, indicating that the observed protection was not due to activation of NK cells and that TNF-alpha is involved in the regulation of antiviral mechanisms other than the activation of interferons. Although additional production of interferon induced by TNF-alpha cannot be excluded, an antiviral effect of TNF-alpha on the course of HSV-1 infection may be postulated from our data.