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Improved cell survival by the reduction of immediate-early gene expression in replication-defective mutants of herpes simplex virus type 1 but not by mutation of the virion host shutoff function

Improved cell survival by the reduction of immediate-early gene expression in replication-defective mutants of herpes simplex virus type 1 but not by mutation of the virion host shutoff function

Journal of Virology 68(10): 6347-6362

ISSN/ISBN: 0022-538X

PMID: 8083974

Derivatives of herpes simplex virus type I (HSV-1) have elicited considerable interest as gene transfer vectors because of their ability to infect a wide range of cell types efficiently, including fully differentiated neurons. However, it has been found that infection of many types of cell with vectors derived from replication-defective mutants of HSV-1 is associated with cytopathic effects (CPE). We have previously shown that viral gene expression played an important role in the induction of CPE caused by an HSV-1 mutant deleted for the essential immediate-early gene 3 (IE 3) (P. A. Johnson, A. Miyanohara, F. Levine, T. Cahill, and T. Friedmann, J. Virol. 66.2952-2965, 1992). We have investigated which viral genes might be responsible for CPE by comparing the ability of each of the individual genes expressed by an IE 3 deletion mutant during a nonproductive infection to inhibit biochemical transformation after cotransfection of BHK or CV-1 cells with a selectable marker gene. Transfection of IE genes 1, 2, and 4 individually all caused a marked inhibition of colony formation, while transfection of IE 5 and the large subunit of ribonucleotide reductase had little effect. These results suggested that it would be necessary to mutate or reduce the expression of nearly all HSV-1 IE genes to reduce virus-induced CPE. Therefore, we have used VP16 mutants, which are unable to transinduce IE gene expression (C. I. Ace, T. A. McKee, J. M. Ryan, J. M. Cameron, and C. M. Preston, J. Virol. 63:2260-2269, 1989), to derive two replication-defective strains: 14H-DELTA-3, which is deleted for both copies of IE 3, and in 1850-DELTA-42, which has a deletion in the essential early gene UL42. The IE 3-VP16 double mutant, 14H-DELTA-3, is significantly less toxic than a single IE 3 deletion mutant over a range of multiplicities of infection, as measured in a cell-killing assay, and has an enhanced ability to persist in infected cells in a biologically retrievable form. In contrast, the UL42-VP16 double mutant, in1850-DELTA-42, showed reduced toxicity only at low multiplicities of infection. To test the role of the virion host shutoff function as an additional candidate to influence virus-induced CPE, we have introduced a large insertion mutation into the virion host shutoff gene of an LE 3 deletion mutant and the double mutant 14H-DELTA-3. Mutation of this gene did not reduce the cytotoxicity of either strain. These results demonstrate that long-term survival of cells infected with replication-defective HSV-1 mutants can be enhanced through genetic manipulations that reduce viral gene expression.

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Accession: 008830673

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