# Impact of HCMV proteins on viral replication and cellular signaling pathways

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $369,378

## Abstract

PROJECT SUMMARY
Human cytomegalovirus (HCMV) infects up to 90% of the U.S. population, resulting in lifelong chronic 
infection. In immunosuppressed individuals, the outcome is more severe, with lifelong persistent infection 
associated with various pathologies. HCMV is also a leading viral cause of congenital birth defects. Several 
antiviral treatments exist, but their use is limited due to significant toxicity, teratogenic effects, poor oral availability
and emergence of antiviral resistance. An HCMV vaccine has yet to be licensed. Thus there is a need to 
understand the mechanism of HCMV infection to establish new targets and approaches for vaccines and 
therapies.
Persistent HCMV infection is complex, involving a balance between productive lytic replication and a silent
latent infection involving genome maintenance without replication. The long-term goal is to elucidate 
mechanisms used by HCMV proteins to control replication and cellular stress responses that influence the fate of
infection. Defining these molecular events will augment understanding of the HCMV infected cell and 
facilitate development of antiviral strategies to manage infection. The experiments presented herein will define
the dynamic and antagonistic regulatory relationships between the HCMV kinase pUL97 and pUL27, and 
determine how this network controls HCMV viral DNA synthesis. HCMV pUL97 regulates pUL27, Tip60 
acetyl-transferase and the downstream effector, p21Cip1. The hypothesis is that pUL97 kinase activates 
Tip60-dependent chromatin remodeling while also inhibiting the pUL27-mediated degradation of Tip60 and
the corresponding p21Cip1 expression to promote viral DNA synthesis. This will be tested in three 
specific aims: Aim 1 Test the hypothesis that pUL27 induces p21Cip1 and prolonged p21Cip1 expression inhibits
factors involved in viral DNA synthesis; Aim 2 Test the hypothesis that pUL97 activation of Tip60 promotes
viral DNA synthesis in a manner that involves chromatin modifications; and AIM 3 Test the hypothesis that
the pUL27-Tip60-pUL97 axis regulates entry into and exit from HCMV latency. A comprehensive repertoire
of cellular and molecular biological techniques, viral genetic analysis, transcriptomics, and quantitative 
“bottom up” and “top down” proteomics will be used to study both lytic and latent models of HCMV infection.
These studies will define how pUL97 kinase promotes viral DNA synthesis and how the antagonistic activities
of two HCMV proteins, pUL97 and pUL27, regulate Tip60 and p21Cip1 expression and control HCMV 
replication. Understanding this regulatory switch will elucidate the mechanism by which therapeutics may silence
HCMV replication.

## Key facts

- **NIH application ID:** 9955149
- **Project number:** 5R01AI083281-09
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Scott Sletten Terhune
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $369,378
- **Award type:** 5
- **Project period:** 2011-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9955149

## Citation

> US National Institutes of Health, RePORTER application 9955149, Impact of HCMV proteins on viral replication and cellular signaling pathways (5R01AI083281-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9955149. Licensed CC0.

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