The mechanisms of ablation of antiviral effects of interferon by herpes simplex virus type 1

Interferons (IFNs) are a major host response to infection by viruses, intracellular bacteria and parasites. IFNs signal the induction of a vast array of genes whose function is to suppress the replication or spread of the invading organism. Most infectious agents have evolved a mechanism by which they counteract the effects of IFNs. The studies described in this dissertation centered on the functions encoded by herpes simplex virus 1 (HSV-1) that render viral replication resistant to interferon. The results were as follows: (i) IFNs activate the induced Jak/Stat signaling pathway. Analyses of the components of this signaling pathway indicate that both Jak1 and Stat2 disappear after infection. Jak1 disappears within the first few hours after infection. The disappearance of Jak1 correlates with the presence of the protein product of the U_L41 open reading frame known also as virion host shutoff (vhs) protein. Vhs forms a complex with a host protein and acts as an RNase. Vhs acts to preclude replenishment of Jak1 whose half-life is relatively short. Jak1 may not be the only target of vhs protein since ectopic overexpression of Jak1 did not restore sensitivity to IFNs. (ii) The infected cell protein No. 0 (ICP0), the product of the viral α0 gene has also been reported to confer resistance to IFNs. ICP0 has been shown to disperse the nuclear structures known as ND10 and to cause degradation of promyelocytic leukemia (PML) protein. PML acts as the organizing protein of ND10 and is involved in the IFN response to infection. Earlier studies have shown that overexpression of PML had no effect on viral replication. To test the hypothesis that the normal amounts of PML are sufficient to enable IFN to mediate the antiviral response, we tested the effect of IFNs on wild-type (PML+/+) and PML knockout (PML−/−) murine fibroblasts. IFN had a significantly greater effect in PML+/+ than in PML−/− infected cells. These results are consistent with the hypothesis that ND10 structures and PML play a role in the interferon response, and that one objective of triggering the dispersal of ND10 and degradation of PML is to preclude this response.