Herpes simplex virus gene products involved in the induction of chromosomal aberrations

The effect of short-term herpes simplex virus type 1 (HSV-1) infection on chromosomes of human diploid fibroblasts was examined. In addition to chromosomal breaks, gaps and pulverization, three kinds of cytogenetic damage (double minutes, polyploidy and endoreduplication) not yet reported following productive infection with HSV or other animal viruses were frequently observed. Consistent with previous studies suggesting that the expression of immediate-early and/or early viral gene products is required for the induction of chromosomal damage, was the observation that cells infected at the nonpermissive temperature with HSV-1 temperature-sensitive mutants defective in the gene for the immediate-early transcriptional regulatory protein, ICP4, and three early viral gene products--DNA polymerase (pol), the major HSV DNA-binding protein (ICP8) and an HSV-2 mutant defective in alkaline nuclease--exhibited altered patterns of chromosomal damage relative to the effects of wild-type virus on infected cells. These findings suggest a direct or indirect role for all four gene products in the induction of chromosomal damage. In cells infected with wild-type virus for 4 h or longer, HSV proved to be a more potent mitotic arresting agent than colcemid. Moreover, studies with selected mutants indicate that HSV pol specifically may be involved in mitotic arrest. Additionally, in cells infected at the non-permissive temperature with a pol mutant, the number of polyploid metaphases was reduced 4-fold relative to that seen in wild-type virus-infected cells suggesting a role for HSV pol in the amplification of cellular DNA.