Studies of latent infection of herpes simplex virus and protein kinase

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Protein kinases (PKs) are involved in a wide variety of functions in eukaryotic cells. These include metabolism, cell cycle, hormone response, and control of transcription and translation. The most commonly studied eukaryotic PKs are those which modify serine and threonine residues and those which modify tyrosine residues. It has been shown that a number of proteins of herpes simplex virus type 1 (HSV- 1) are phosphorylated and HSV-1 encodes viral PKs, but the role of phosphorylation of viral proteins in HSV-1 infection has not been clarified. In the present study, the effects of PK inhibitors including protein tyrosine kinase (PTK) inhibitors, genistein and tyrphostin, and protein kinase C (PKC) inhibitor, 1-(5-isoquinoline- sulfonyl)-2-methylpiperazine (H-7), on the replication of HSV-1 and phosphorylation of viral proteins were examined. Genistein and prunetin which inhibit PTK inhibited the replication of HSV-1 at genistein concentrations of more than 25muM,whereas the related comp … More ounds, which do not inhibit PTK,did not affect the replication of HSV-1. Tyrphostins 9,47, B42, and B46, synthetic inhibitors of PTKs, all inhibited the plaque formation of HSV-1, but Tyrphostin 9, B42 and B46 exhibited more selective antiviral effect. Infected cell polypeptides (ICP) 6,17/18,19/20, and 25 were found to be tyrosine-phosphorylated proteins. The HSV-1 proteins which have phosphorylated tyrosine residues and suppressed by tyrphostin 9 most significantly were the products of the UL47 gene, the tegument proteins VP13/14. PKC inhibitor H-7 also inhibited the replication of HSV-1. On the other hand, PKC activator 12-o-teradecanoyl phorbol-13-acetate enhanced the HSV-1-induced syncytium formation in A431 epidermoid carcinoma cells, suggesting that PKC activation promotes the development of multinucleated giant cells in herpetic muco-cutaneous lesions. In this project, animal models of oral and salivary gland tumors were also established. In future, we will test the inhibitory effect of above described PK inhibitors on both HSV-1 and tumor formation in vivo. Less