The baculoviruses are a family of large DNA viruses distinguished by their prolific multiplication and novel interactions with the host insect. As such, these nuclear-replicating viruses are used as efficient vectors for foreign gene expression, potent biological insecticides, and sources of genes with unique biological properties that include regulation of programmed cell death. To insure replicative success, the baculoviruses employ novel mechanisms that exploit the host biosynthetic machinery to expedite viral expression and suppress host defenses. It is the long term goal of this study to investigate the molecular interactions between the baculovirus and its host cell by defining the mechanisms by which Autographa californica nuclear polyhedrosis virus (AcMNPV) regulates early gene expression and evades the host apoptotic response. In an integrated set of experiments that use biochemical, genetic and cell biology approaches, the molecular mechanisms by which AcMNPV transcriptional regulators accelerate virus replication will be investigated. An extensive series of loss-of-function mutations in the principal transactivator IE1 will be used to examine the molecular interaction between transactivator and AcMNPV enhancer elements and to determine the mechanism of transcriptional stimulation. By using stably transfected cells that express dominant negative inhibitors of IE1, the role of IE1 during AcMNPV infection will be determined. Early and late baculovirus replicative events trigger apoptosis by unknown mechanisms. By using AcMNPV-infected cells and the baculovirus apoptotic regulators p35 and iap in a powerful yet convenient approach, the signals responsible for virus induced apoptosis will be defined. The pro-apoptotic activity of isolated viral genes will be evaluated in transfection assays and new viral mutants defective for apoptotic induction will be characterized. These studies will be complemented by the investigation of apoptotic pathways induced by UV radiation and DNA damaging agents to compare the death signals induced by baculovirus infection. Collectively, these studies are expected to provide important insight into pathways responsible for apoptosis, a process that constitutes a major contribution to the pathogenicity of human viruses. Moreover, as determined here, the molecular mechanism by which baculoviruses regulate early gene transcription are directly applicable to insect vectors of human disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Experimental Virology Study Section (EVR)
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Meegan, James M
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University of Wisconsin Madison
Other Domestic Higher Education
United States
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Byers, Nathaniel M; Vandergaast, Rianna L; Friesen, Paul D (2016) Baculovirus Inhibitor-of-Apoptosis Op-IAP3 Blocks Apoptosis by Interaction with and Stabilization of a Host Insect Cellular IAP. J Virol 90:533-44
Vandergaast, Rianna; Mitchell, Jonathan K; Byers, Nathaniel M et al. (2015) Insect inhibitor-of-apoptosis (IAP) proteins are negatively regulated by signal-induced N-terminal degrons absent within viral IAP proteins. J Virol 89:4481-93
Mitchell, Jonathan K; Byers, Nathaniel M; Friesen, Paul D (2013) Baculovirus F-box protein LEF-7 modifies the host DNA damage response to enhance virus multiplication. J Virol 87:12592-9
Taggart, David J; Mitchell, Jonathan K; Friesen, Paul D (2012) A conserved N-terminal domain mediates required DNA replication activities and phosphorylation of the transcriptional activator IE1 of Autographa californica multicapsid nucleopolyhedrovirus. J Virol 86:6575-85
Mitchell, Jonathan K; Friesen, Paul D (2012) Baculoviruses modulate a proapoptotic DNA damage response to promote virus multiplication. J Virol 86:13542-53
Vandergaast, Rianna; Schultz, Kimberly L W; Cerio, Rebecca J et al. (2011) Active depletion of host cell inhibitor-of-apoptosis proteins triggers apoptosis upon baculovirus DNA replication. J Virol 85:8348-58
Kopek, Benjamin G; Settles, Erik W; Friesen, Paul D et al. (2010) Nodavirus-induced membrane rearrangement in replication complex assembly requires replicase protein a, RNA templates, and polymerase activity. J Virol 84:12492-503
Cerio, Rebecca J; Vandergaast, Rianna; Friesen, Paul D (2010) Host insect inhibitor-of-apoptosis SfIAP functionally replaces baculovirus IAP but is differentially regulated by Its N-terminal leader. J Virol 84:11448-60
Schultz, Kimberly L W; Friesen, Paul D (2009) Baculovirus DNA replication-specific expression factors trigger apoptosis and shutoff of host protein synthesis during infection. J Virol 83:11123-32
Schultz, Kimberly L W; Wetter, Justin A; Fiore, Diccon C et al. (2009) Transactivator IE1 is required for baculovirus early replication events that trigger apoptosis in permissive and nonpermissive cells. J Virol 83:262-72

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