title: Induction of cellular stress overcomes the requirement of herpes simplex virus type 1 for immediate-early protein ICP0 and reactivates expression from quiescent viral genomes.
abstract: Herpes simplex virus type 1 (HSV-1) mutants impaired in the activities of the structural protein VP16 and the immediate-early (IE) proteins ICP0 and ICP4 establish a quiescent infection in human fibroblasts, with most cells retaining an inactive, repressed viral genome for sustained periods in culture. To date, the quiescent state has been considered stable, since it has been reversed only by provision of herpesviral proteins, such as ICP0, not by alteration of the cell physiological state. We report that the interaction of HSV-1 with human fibroblasts can be altered significantly by transient treatment of cultures with sodium arsenite, an inducer of heat shock and oxidative stress, or gramicidin D, a toxin that selectively permeabilizes cell membranes, prior to infection. These regimens stimulated gene expression from IE-deficient HSV-1 mutants in a promoter sequence-independent manner and also overcame the replication defect of ICP0-null mutants. Reactivation of gene expression from quiescent HSV-1 genomes and the resumption of virus replication were observed following addition of arsenite or gramicidin D to cultures. Both agents induced reorganization of nuclear domain 10 structures, the sites of quiescent genomes, but appeared to do so through different mechanisms. The results demonstrate that the physiological state of the cell is important in determining the outcome of infection with IE-deficient HSV-1 and show novel methods for reactivating quiescent HSV-1 in fibroblasts with a high efficiency.
authors.affiliation: Medical Research Council Virology Unit, Church Street, Glasgow G11 5JR, Scotland, United Kingdom. c.preston@mrcvu.gla.ac.uk
authors.forename: Chris M
authors.initials: CM
authors.lastname: Preston
authors.forename: Mary Jane
authors.initials: MJ
authors.lastname: Nicholl
mesh_terms: D017209:Apoptosis; D018053:Arsenites / Q000494:pharmacology; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000235:genetics; D017781:Genes, Immediate-Early; D016679:Genome, Viral; D006096:Gramicidin / Q000494:pharmacology; D018259:Herpesvirus 1, Human / Q000235:genetics* / Q000502:physiology; D006801:Humans; D017874:Immediate-Early Proteins / Q000502:physiology*; D011401:Promoter Regions, Genetic; D013312:Stress, Physiological; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D014775:Virus Activation
chemical_list: D018053:Arsenites; D017874:Immediate-Early Proteins; D006096:Gramicidin; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1; C015001:arsenite
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