This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Herpes simplex virus (HSV) is a common and significant pathogen, which causes cold and genital sores and blindness. The lifecycle of HSV has two distinct phases: lytic and latent infections. A pivotal HSV protein in determining the switch between lytic and latent infections is infected cell protein 0 (ICP0). ICP0 is a 110-KDa nuclear phosphoprotein that strongly transactivates viral gene expression, degrades cellular proteins in nuclear domain (ND) 10, and inhibits the anti-viral response of cellular interferons (IFNs). IFNs are secreted cellular immunomodulatory factors that upregulate the expression of ND10-associated proteins to limit the spread and replication of viruses. Genetics studies have indicated that the ND10-associated protein, promyelocytic leukemia (PML), plays an important role in IFN-mediated inhibition of HSV replication. Thus, ICP0 and PML interactions via IFNs likely govern the type of infection HSV will establish. The long-term goal of our studies is to understand at the molecular level how virus-cell interactions affect HSV infection. The objective of this proposal is to determine how ICP0 and PML interactions modulate the virus-host response. Our central hypothesis is that ICP0 impairs the anti-viral activity of PML that, in turn, is required for efficient viral replication. To test this hypothesis, we will use a variety of genetic, biochemical, and cell biology approaches. For this purpose, we will determine the contributions of PML (Aim 1) and ICP0 (Aim 2) motifs in regulating the virus-host response. Results from these studies are expected to lead to novel anti-viral therapies.
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