ANTIVIRAL ACTIVITY OF TUMOR-NECROSIS-FACTOR (TNF) IS MEDIATED VIA P55AND P75 TNF RECEPTORS

The antiviral nature of tumor necrosis factor (TNF) is generally well accepted. TNF appears to induce multiple antiviral mechanisms, and to synergize with interferon (IFN)-gamma in promoting antiviral activitie s. We infected TNF receptor (TNFR)-deficient mice with the virulent mu rine pathogen, ectromelia virus (EV), and observed that otherwise resi stant mice were susceptible to lethal infection. To study the molecula r basis of the antiviral action of TNF, mice were infected with a reco mbinant vaccinia virus encoding murine TNF (VV-HA-TNF). In normal mice , the replication of VV-HA-TNF was highly attenuated. In contrast, mic e in which the TNFR type 1 (p55) or the TNFR type 2 (p75) were genetic ally disrupted showed a moderate defect in their capacity to clear the TNF-encoding virus. The contribution of both TNF receptors to the con trol of VV-HA-TNF was confirmed by the enhanced replication of VV-HA-T NF in mice deficient for both p55 and p75. These observations were cor roborated by infecting TNFR-deficient mice with EV. For both infection s, the p55 and p75 TNFRs were necessary to maintain normal levels of r esistance. Thus, the antiviral activity of TNF is mediated via both TN FRs in vivo. Furthermore, these studies establish that TNF is an impor tant component of the host response to a natural virus infection.