The herpes simplex virus major regulatory protein ICP4 blocks apoptosis induced by the virus or by hyperthermia.
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 alpha 4 (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) Vero cells infected with wild-type HSV-1(F) or cells expressing the alpha 4 gene and infected with the alpha 4- virus did not exhibit apoptosis; (iii) fragmentation of cellular DNA was observed in Vero cells that were mock-infected or infected with the alpha 4- virus and maintained at 39.5 degrees 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 alpha 4 gene and at 39.5 degrees C only alpha genes are expressed. These results indicate that the product of the alpha 4 gene is able to suppress apoptosis induced by the virus as well by other means.
Leopardi
R
R
Marjorie B. Kovler Viral Oncology Laboratories, University of Chicago, IL 60637.
Roizman
B
B
D000818:Animals; D017209:Apoptosis; D002522:Chlorocebus aethiops; D004587:Electrophoresis, Agar Gel; D017874:Immediate-Early Proteins / Q000235:genetics / Q000502:physiology*; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D018139:Simplexvirus / Q000235:genetics / Q000502:physiology*; D013696:Temperature; D014709:Vero Cells
D017874:Immediate-Early Proteins; C048925:herpes simplex virus, type 1 protein ICP4