Human cytomegalovirus (HCMV) infection permanently afflicts over half of all Americans, is the most common infectious cause of birth defects, and threatens the lives of thousands of children and adults with impaired immune systems. New strategies to stop the infection are urgently needed because current antiviral drugs are inadequate and a vaccine is non-existent. Our ultimate goal is to discover ways of immediately blocking HCMV infection, which may be reasonably achieved through selective disruption of viral gene expression. Toward this goal, the objective of this research project is to determine the mechanisms utilized by HCMV to regulate transcription of its genome during the course of an active infection. We hypothesize that HCMV adopts the basic host principles of transcription control of the RNA polymerase II, but modifies this host machinery through the actions of viral products. We further hypothesize that the major HCMV MIE proteins are central to orchestrating the temporal cascade of viral transcription, while also differentially modulating host transcription. The planned experiments will examine in-depth the transcriptional regulation of both HCMV and host genomes using powerful global techniques (ChIP-Seq, PRO-Seq, and RNA-Seq), novel in vitro systems (customized nuclear walk-on assays), originally crafted reagents (HCMV mutants), and a newly developed technology for rapidly and robustly eliminating proteins of interest to unravel their role in HCMV transcriptional regulation. The plan integrates the biochemical and molecular expertise of the Price Lab in transcription control and global techniques and the extensive experience of Meier Lab in HCMV virology and gene expression. The results of these experiments will be the first to determine the extent to which HCMV applies recently discovered mechanisms controlling animal gene expression, as well as the roles of the HCMV MIE proteins in commandeering this vital process. Results obtained through the combined efforts of the Meier and Price Labs will be applicable to understanding transcriptional regulation not only of HCMV, but all DNA viruses. The work proposed here will set the groundwork for future studies aimed at controlling infections of HCMV, HSV, EBV, and other viruses.

Public Health Relevance

Cytomegalovirus (CMV) infection kills or disables thousands of American children and adults every year. Current antiviral drugs are not effective enough against CMV and there are no anti-CMV vaccines. Our ultimate research goal is to discover unique druggable targets that will effectively deactivate the virus at its earliest stages, thereby blocking new infections and flare-ups from old infections..

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI130453-02
Application #
9617218
Study Section
Virology - A Study Section (VIRA)
Program Officer
Beisel, Christopher E
Project Start
2017-12-20
Project End
2019-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Price, David H (2018) Transient pausing by RNA polymerase II. Proc Natl Acad Sci U S A 115:4810-4812