FUNCTIONAL INTERACTIONS BETWEEN HERPES-SIMPLEX VIRUS IMMEDIATE-EARLY PROTEINS DURING INFECTION - GENE-EXPRESSION AS A CONSEQUENCE OF ICP27 AND DIFFERENT DOMAINS OF ICP4

Two of the five immediate-early gene products, ICP4 and ICP27, express ed by herpes simplex virus type 1 have profound effects on viral gene expression and are absolutely essential for virus replication. Functio nal interactions between ICP4 and ICP27 may contribute to establishing the program of viral gene expression that ensues during lytic infecti on. To evaluate this possibility, viral mutants simultaneously deleted for ICP27 and defined functional domains of ICP4 were constructed. Th ese mutant viruses allowed a comparison of gene expression as a functi on of different domains of ICP4 in the presence and absence of ICP27. Gene expression in the absence of both ICP4 and ICP27 was also examine d. The results of this study demonstrate a clear involvement for ICP27 in the induction of early genes, in addition to its known role in enh ancing late gene expression during viral infection. In the absence of both ICP4 and ICP27, viral early gene expression, as measured by the a ccumulation of thymidine kinase and ICP6 messages was dramatically red uced relative to the amounts of these messages seen in the absence of only ICP4. Therefore, elevated levels of early gene expression as a co nsequence of ICP27 occurred in the absence of any ICP4 activity. Evide nce is also presented regarding the modulation of the ICP4 repression function by ICP27. When synthesized in the absence of ICP27, a mutant ICP4 protein was impaired in its ability to repress transcription from the L/ST promoter in the context of viral infection and in vitro. Thi s defect correlated with the loss of the ability of this mutant protei n to bind to its recognition sequence when produced in infected cells in the absence of ICP27. These observations indicate that ICP27 can re gulate the activity of at least one domain of the ICP4 protein as well as contribute to elevated early gene expression independently of ICP4 .