Productive infection by herpes simplex virus (HSV) is stimulated by the virally-encoded transcription factor VP16, which associates with the cellular transcription factor HCF-1 to form a multiprotein-DNA complex on each of the five viral immediate-early (IE) gene promoters. Failure of HSV to express sufficient levels of IE gene products may lead to the establishment of a latent infection in appropriate cell types such as sensory neurons. The importance of HCF-1 to the viral productive cycle is most clearly demonstrated by infection of cells with a conditionally inactivated version of HCF-1. This results in a significant delay in viral gene expression and severely reduced virus yield. Dr. Wilson proposes that differences in the activity or localization of HCF-1 in sensory neurons contribute to the establishment or maintenance of viral latency. In these cells, HCF-1 is found predominantly in cytoplasm, a striking contrast to most other cell types where HCF-1 is predominantly nuclear. Signals that promote reactivation also trigger a rapid relocalization of HCF-1 to the nucleus. To this end, they have identified a novel HCF-1 associated protein with characteristics of a nucleocytoplasmic shuttle factor that may be responsible for the dynamic localization of HCF-1 in neurons. Regulation of HCF-1 localization may also be important in other contexts. HCF-1 is required for transcriptional activation by a number of DNA-binding proteins and loss of HCF-1 leads to an arrest in G1 phase of the cell cycle.
The aims of this proposal are to:
(Aim 1) understand how VP16 and the novel shuttle protein (designated HPIP) selectively target HCF-1 rather than the close-relative HCF-2;
(Aim 2) demonstrate suppression of IE gene expression by the candidate shuttle proteins (HPIP) and establish its mode of action in sensory neurons and other cell types;
and (Aim 3) test the hypothesis that HCF-1 stimulates IE gene activation by interacting with additional transcription factors bound to sites flanking the VP16-responsive elements in each IE promoter. The investigator suggests that the pivotal role of HCF-1 in initiating viral IE gene expression represents an important target for the design of new therapeutic strategies to combat human diseases that arise from HSV infection.
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