UL34 AND HERPES SIMPLEX VIRUS INFECTION

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Herpes simplex viruses (HSVs) are widely distributed human pathogens. Serological studies suggest that at least 50 percent of the american adult population have antibodies to at least one of the two herpes simplex viruses, indicating infection at some time. The severity of disease ranges from asymptomatic to lethal, depending upon the age and immune competence of the infected individual. Control of herpes simplex viruses and related herpesviruses can be improved by understanding the functions of the virus-encoded proteins, and the mechanisms by which those products are regulated in the infected cell. The research proposed here will identify the function of the product of the essential UL34 gene. Preliminary studies have shown that the UL34 protein is a membrane associated protein whose timing of synthesis and localization in the cell suggest a function in envelopment or egress. These studies will entail the construction and characterization of UL34-deficient viruses, and identification of cellular proteins that interact with, and are regulated by the UL34 protein. These results should, in turn, illuminate the function of the regulatory events mediated by the US11 and US3 proteins, which regulate these products of the UL34 gene. The proposed research is novel and likely to be highly medically significant from several points of view. (i) The UL34 gene product is conserved among alphaherpesviruses including varicella zoster virus (VZV) and is very likely an essential virus gene product for replication in cell culture and in the human host. Its function, therefore, represents a potential therapeutic target. (ii) The function of the UL34 gene product is apparently regulated by phosphorylation, and UL34, in turn appears to regulate the phosphorylation of cellular proteins. Regulation of phosphorylation is a ubiquitous strategy for controlling a wide range of cellular processes, and these studies are likely to expose a novel example of viral regulation of cellular phosphorylation. (iii) The UL34 locus is regulated by the US11 RNA binding protein. Specific RNA-protein interactions like that involved in US11-mediated regulation of transcripts from the UL34 gene are critical in regulating many processes important to the control of cell proliferation (including regulation of oncogene activity), and in regulating the infection of lymphotropic retroviruses. These studies will contribute to the understanding of the ways in which RNA-protein interactions give rise to regulatory effects.