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 α (TNF-α). Mice pretreated with 100 ng, or even 10 ng, of TNF-α showed prolonged survival compared to control mice that were infected with 10 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-α 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-α and there was no enhanced interferon titre in mice treated with both TNF-α and HSV-1, suggesting some interferon-independent protection. However, mice treated with TNF-α 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-α-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-α is involved in the regulation of antiviral mechanisms other than the activation of interferons. Although additional production of interferon induced by TNF-α cannot be exclusded, an antiviral effect of TNF-α on the course of HSV-1 infection may be postulated from our data


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