The regulation of herpes simplex virus type 1 (HSV-1) gene expression is a highly complex process. Following primary exposure or reactivation, HSV-1 undergoes lytic growth, during which it can cause a wide spectrum of human diseases ranging from minor skin ulcerations to fatal neonatal and central nervous system diseases. On the other hand, the virus can remain latent and undetectable in the trigeminal ganglion for the life of an individual. It is clear that HSV-1 gene expression is regulated differently during these two phases of viral infection. In addition, lytic HSV-1 infection of tissue culture cells in vitro is regulated in a complex manner. Viral encoded inducers act on specific sequences in the promoter-regulatory regions of HSV-1 genes to modulate expression of those genes. To identify the specific sequences involved in the regulation of an HSV-1 early gene and to analyze the interaction of specific inducers with those sequences, the regulation of the glycoprotein D (gD) gene will be studied. To do this, a series of alteration will be introduced into the regulatory region of the gD gene. The effects of these regulatory alterations will be determined by examining transient expression of gD following transfer of the gD gene to mammalian cells, by analyzing gD expression in stably transformed cell lines, and by studying gD regulation during viral infection. Induction of GD expression in the transient expression assays and in the stable cell lines will be accomplished by infection with HSV-1. During such infection, it is known that the oc gene product ICP4 is the primary inducer, so the sequences that interact with ICP4 will be investigated. However, preliminary studies suggest that gD may also be induced by two other oc products, ICP22 and ICP47, even though no inducer activity has previously been demonstrated for either of these two genes. In stable cell lines containing the genes for ICP22 and ICP47 along with the gene for gD, ICP22 and/or ICP47 induced gD expression. We will continue these studies to determine which of these proteins acts as the inducer, and if the sequences in the gD regulatory region which respond to ICP22/ICP47 induction are the same ones which respond to ICP4 induction.
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