Inhibition by Interferon of Herpes Simplex Virus Thymidine Kinase and DNA Polymerase in Infected and Biochemically Transformed Cells

Abstract

SUMMARYThe induction of thymidine kinase (TK) and DNA polymerase was inhibited by interferon (IFN) in mouse L-cells infected with herpes simplex virus type 1 (HSV-1). The inhibitory activity of IFN at this early stage of HSV-1 replication was followed by a reduced virus yield and was dependent on the multiplicity of infection.The expression of a cloned thymidine kinase (tk) gene of HSV-1, in biochemically transformed L-cells (LTK+), was not affected by IFN. These same LTK + cells, however, developed an antiviral state since, upon HSV-1 infection, the induction of TK and DNA polymerase of the replicating virus was inhibited by IFN. Furthermore, IFN inhibited the transactivation of the HSV-1 tk gene in the biochemicaUy transformed LTK + cells, which followed infection by a virus mutant defective in the tk gene (HSV-1 TK-). This transactivation is dependent on expression of immediate-early HSV-1 s-genes. These results indicate that IFN inhibits HSV-I replication at an early step prior to DNA synthesis. In addition, IFN displays a differential effect on the HSV-1 thymidine kinase gene, either when part of the replicating virus or when expressed as a cellular gene in biochemically transformed cells.

Inhibition of Replication of Herpes Simplex Virus in Mouse Macrophages by Interferons

“…Similar findings have been made with mouse L-cells (Panet & Falk, 1983) and human HeLa cells (Gloger & Panet, 1984). Contrary to these findings Mufioz & Carrasco (1984) reported no inhibition of HSV protein synthesis by IFN in HeLa cells which led them to suggest that IFN acts via the production of defective virions during the first virus cycle.…”

“…One reason for selecting these cells was the sensitivity of the macrophage-HSV system to IFN. Compared to other systems (Panet & Falk, 1983;Rasmussen et al, 1984) inhibition of HSV in mouse macrophages by IFN was much more effective. Previously, most experiments concerning IFN-mediated inhibition of HSV replication were done in permanent cell lines (Lerner & Bailey, 1976;Fish et al, 1983).…”

“…Enzyme activities were determined as described by Panet & Falk (1983) and Purifoy & Benyesh-Melnick (1975). The incorporation of [3H]TTP (sp.…”

Inhibition of Transcription of Herpes Simplex Virus Immediate Early Genes in Interferon-treated Human Cells

“…Although the different cells varied in their sensitivity to IFN, the level of HSV-I inhibition was 10-to 100-fold. As shown previously for HSV-l-infected mouse L cells, IFN suppressed the synthesis of the early/~ proteins, TK and DNA polymerase (Panet & Falk, 1983). Furthermore, in HeLa cells, the induction of both HSV-1 immediate early ~ and early/~ proteins was inhibited by pretreatment of the cells with IFN (Gloger & Panet, 1984).…”

“…Several studies using a variety of cell lines have indicated that the replication of HSV-1 is inhibited by IFN, as determined by the plaque reduction assay (Cayley et al, 1984;Domke et al, 1985;Gloger & Panet, 1984;Panet & Falk, 1983). Although the different cells varied in their sensitivity to IFN, the level of HSV-I inhibition was 10-to 100-fold.…”