Human cytomegalovirus (CMV) is the most common cause of non-hereditary sensorineural hearing loss in the U.S. Current therapies to treat infection during pregnancy or upon birth are unproven and risky. The experimental antiviral compound maribavir is a specific inhibitor of the CMV protein kinase, pUL97, and exhibits low toxicity. The objective of my proposal is to identify the molecular mechanism behind pUL97 kinase-mediated regulation of CMV gene expression and determine the impact of inhibiting kinase activity on CMV infected embryonic stem cell-derived neuronal progenitor cells. I have demonstrated that inhibition of the CMV kinase resulted in decreased expression of viral immediate early (IE) genes. This is a newly identified function of the CMV pUL97 kinase. Our lab previously identified an interaction between the CMV pUL97 kinase and cellular histone deacetylase 1 (HDAC1). HDAC1 acts as a repressor and is recruited to the MIE promoter at early times during infection. Therefore, I hypothesize that the kinase activity of CMV pUL97 influences the histone modification pattern at the viral major immediate early promoter by altering cellular HDAC1 activity. I propose to evaluate the pUL97-dependent changes of histone modifications at the major immediate early promoter (MIEP) during infection. These studies will be initiated using human diploid fibroblasts. In addition, I will identify pUL97-mediated changes in HDAC1 localization within the infected cells and at the MIEP. Other herpesvirus kinases phosphorylate HDAC1 and I propose several approaches to identify potential changes in HDAC1 phosphorylation by pUL97. I will determine the impact of these changes on HDAC1 deacetylase activity. I will further these studies using an embryonic stem cell-derived neural progenitor cell line (ES-NPCs) as a model system for CMV-induced neurological damage due to congenital CMV infection. Expression of IE genes has been demonstrated to alter fetal/neonate NPC differentiation. CMV IE genes regulate cell cycle and apoptosis in human diploid fibroblasts. I will test the role of pUL97 during these early events in the context of ES-NPC's by confirming the major results that were obtained in our fibroblast studies. I will determine the effectiveness of maribavir in preventing the pathogenic effects of HCMV infection on neuronal development. My studies will determine if a pUL97 kinase inhibitor is suitable for treating CMV infected neonates and possibly CMV infected mothers at risk of congenital infection.

Public Health Relevance

Congenital cytomegalovirus (CMV) infection occurs in 1 out of 150 pregnancies each year in the U.S. Infection results in approximately 400 neonate deaths and 5,500 children with developmental disorders of the central nervous system. We will determine the molecular mechanism behind an event that occurs very early during infection and explore possible ways of blocking that event and preventing infection within neuronal progenitor cells.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Adger-Johnson, Diane S
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Medical College of Wisconsin
Schools of Medicine
United States
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Bigley, Tarin M; McGivern, Jered V; Ebert, Allison D et al. (2016) Impact of a cytomegalovirus kinase inhibitor on infection and neuronal progenitor cell differentiation. Antiviral Res 129:67-73
Bigley, Tarin M; Reitsma, Justin M; Terhune, Scott S (2015) Antagonistic Relationship between Human Cytomegalovirus pUL27 and pUL97 Activities during Infection. J Virol 89:10230-46
Bigley, Tarin M; Reitsma, Justin M; Mirza, Shama P et al. (2013) Human cytomegalovirus pUL97 regulates the viral major immediate early promoter by phosphorylation-mediated disruption of histone deacetylase 1 binding. J Virol 87:7393-408
Mounce, Bryan C; Mboko, Wadzanai P; Bigley, Tarin M et al. (2013) A conserved gammaherpesvirus protein kinase targets histone deacetylases 1 and 2 to facilitate viral replication in primary macrophages. J Virol 87:7314-25