Cytodifferentiating agents affect the replication of herpes simplex virus type 1 in the absence of functional VP16.
The herpes simplex virus type 1 (HSV-1) mutant in1814 encodes an altered form of the virion protein VP16 that is unable to transactivate immediate-early (IE) transcription. As a consequence of the mutation, in1814 initiates productive replication inefficiently after infection of tissue culture cells. Previous studies showed that this defect could be overcome by the inclusion in the culture medium of hexamethylene bisacetamide (HMBA), a compound that promotes the differentiation of murine erythroleukemia cells (MELCs). The effects of additional agents known to induce differentiation of MELCs were investigated. N'-Methylnicotinamide, at concentrations optimal for the induction of MELCs, complemented the replication of in1814 and stimulated IE gene expression. Suberoyl bishydroxamic acid and suberoylanilide hydroxamic acid, which induce differentiation of MELCs at micromolar concentrations, did not complement in1814 but specifically blocked the action of HMBA. The histone deacetylase inhibitor trichostatin A, which also induces differentiation of MELCs, antagonized the effect of HMBA in a manner similar to that of suberoyl bishydroxamic acid and suberoylanilide hydroxamic acid. The results demonstrate that the requirement for VP16 activity is dependent on the metabolic state of the host cell and that the pathways leading to complementation of in1814 and differentiation of MELCs are overlapping but not identical.
Preston
C M
CM
Medical Research Council Virology Unit, Church Street, Glasgow, G11 5JR, Scotland. c.preston@vir.gla.ac.uk
McFarlane
M
M
D000081:Acetamides / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D004249:DNA Damage; D017781:Genes, Immediate-Early / Q000187:drug effects; D005814:Genes, Viral; D005816:Genetic Complementation Test; D017405:Herpes Simplex Virus Protein Vmw65 / Q000235:genetics / Q000502:physiology; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D006877:Hydroxamic Acids / Q000494:pharmacology; D051379:Mice; D009154:Mutation; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000187:drug effects* / Q000235:genetics; D000077337:Vorinostat
D000081:Acetamides; D017405:Herpes Simplex Virus Protein Vmw65; D006877:Hydroxamic Acids; D009536:Niacinamide; C012589:trichostatin A; D000077337:Vorinostat; C014026:hexamethylene bisacetamide