The herpes simplex virus major regulatory protein ICP4 blocks apoptosis induced by the virus or by hyperthermia

Abstract

Cells infected with herpes simplex virus 1 (HSV-1) undergo productive or latent infection without exhibiting features characteristic of apoptosis. In this report, we show that HSV-1 induces apoptosis but has evolved a function that blocks apoptosis induced by infection as well as by other means. Specifically, (i) Vero cells infected with a HSV-1 mutant deleted in the regulatory gene α4 (that encodes repressor and transactivating functions), but not those infected with wild-type HSV.1(F), exhibit cytoplasmic blebbing, chromatin condensation, and fragmented DNA detected as a ladder in agarose gels or by labeling free DNA ends with terminal transferase; (ii) Veto cells infected with wild-type HSV-1 (F) or cells expressing the α4 gene and infected with the α4- virus did not exhibit apoptosis; (iii) fragmentation of cellular DNA was observed in Vero cells that were mockinfected or infected with the α4- virus and maintained at 39.5°C, but not in cells infected with wild-type virus and maintained at the same temperature. Wild-type strains of HSV-1 with limited extrahuman passages, such as HSV-1 (F), carry a temperature-sensitive lesion in the α4 gene and at 39.5°C only α genes are expressed. These results indicate that the product of the α4 gene is able to suppress apoptosis induced by the virus as well by other means.