# Mechanisms Regulating Cytomegalovirus

> **NIH VA I01** · IOWA CITY VA MEDICAL CENTER · 2024 · —

## Abstract

Human cytomegalovirus (HCMV) infects over half of all Veterans and threatens the lives of those with
impaired immune systems. HCMV is the leading infectious cause of birth defects. There is no HCMV
vaccine, and the antiviral drugs have problems with potency, toxicity, and drug-resistance. The long-range
goal of this research is to identify critical points in the viral transcription-DNA replication cycle that would
serve as new targets for therapeutic intervention. This proposal is based on the premise that our gap in
knowledge of how viral early transcription produces viral DNA replication and how viral DNA replication
results in viral late transcription limits our ability to design new therapeutic treatments for the viral disease.
By customizing advanced technologies and developing new tools, we have used integrated functional
genomics (dTag system, PRO-Seq, ChIP-Seq, genetically engineered test viruses, and promoter function
assays) to determine where and when Pol II initiates transcription, identify sites of viral transcription factor
binding genome-wide, and quantify change in Pol II nascent transcripts from individual promoters in relation
to core promoter sequences, transcription factor loss, stage of infection, and viral DNA replication. We find
that there are three distinct pathways to viral late transcription. Two of these pathways involve the HCMV
IE2 and late transcription factor (LTF) group members. The individual role of each of the 3 different IE2
isoforms (IE2-86, IE2-60, and IE2-40) in viral late transcription is unknown. The six-member set of LTFs
bind to Pol II and a DNA sequence signature in gene promoters, forming a preinitiation complex (PIC) that
drives transcription. Diversity in sequence signature pattern likely determines the amount of individual
promoter output. It is unknown precisely when and how the LTF complex assembles on viral promoters and
how the LTF assembly engages Pol II in transcription. Our use of a new high-resolution ChIP-Seq technique
and bioinformatics pipeline to map genomic locations of nucleosomes, as well as IE2 and LTF PICs,
suggests that LTF PICs occupy genome regions not occupied by nucleosomes. This new ChIP-Seq
technique will strengthen our integrated functional genomics approach to further determining the
mechanisms controlling viral promoter transcription in relation to chromatin structure. Our preliminary data
indicate that: 1) the early-late transcription switch lags many hours behind the onset of viral DNA replication;
2) the HCMV promoter population members that are active differs by cell type and condition, and this
difference may involve IE2 and LTF functions; and 3) the HCMV promoter population that is active during
viral reactivation in the NT2 model differs from that in acute productive infection. We will test the hypothesis
that HCMV transcription factors usurp host Pol II that navigates a modified chromatin environment suited to
bring about viral late transcription (Aims 1 and 2) an...

## Key facts

- **NIH application ID:** 10721355
- **Project number:** 5I01BX004434-06
- **Recipient organization:** IOWA CITY VA MEDICAL CENTER
- **Principal Investigator:** JEFFERY L MEIER
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-10-01 → 2026-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10721355

## Citation

> US National Institutes of Health, RePORTER application 10721355, Mechanisms Regulating Cytomegalovirus (5I01BX004434-06). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10721355. Licensed CC0.

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