The herpesviruses are the largest and most complex of the known oncogenic DNA viruses and are suspected of having a role either directly, or as cofactors, in the development of cervical carcinoma, Burkitt's lymphoma and nasopharyngeal carcinoma, as well as in a variety of animal tumors. These viruses are also of major concern as reactivated infections and potential tumorgenic agents in AIDS and other immunocompromised patients. Our research focuses on aspects of herpesvirus molecular biology centering around interactions between viral and cellular DNA and gene products that are relevant to how the virus genome (a) usurps control of the cell, (b) causes cell transformation, and (c) establishes a latent state in susceptible neurons, lymphocytes or white blood cells. During the current project period we have opted to concentrate exclusively on reconstruction experiments with cloned intact immediate-early genes and their target promoters to ask specific questions about details of the mechanism of herpes simplex virus early gene regulation. Using both transient expression assays and long-term DNA-transfected cell lines we plan to: (1) explain why the positive non-specific trans-activating properties of the protein product of the isolated IE110 (or ICP0) gene are repressed or dominated by cotransfection with the IE175 (or ICP4) gene, (2) define the mechanism by which the IE110 gene product activates heterologous promoter targets and examine the possible requirements for a particular """"""""state"""""""" of the target DNA, (3) clearly identify the DNA sequence specificity requirements for positive activation of delayed-early class genes by the isolated IE175 gene product and (4) examine further and manipulate the response to cis-acting DNA signals for IE175 negative autoregulation. Knowledged of the detailed mechanism of IE175 and IE110 trans-activation, in comparison with those other nuclear transcriptional regulatory proteins with similar properties (i.e. I1A, T-antigen, v-myc and v myb), should help to explain why some of them act as oncogenes capable of transforming or immortalizing cells, whereas others do not.
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