# Mechanisms regulating cytomegalovirus

> **NIH VA I01** · IOWA CITY VA MEDICAL CENTER · 2021 · —

## Abstract

Human cytomegalovirus (HCMV) infects over half of all Veterans and threatens the lives of those with
impaired immune systems. Even among Veterans with normal immune systems, the insidious reactivation
of the virus taxes the immune system, incites low-level inflammation, and possibly accelerates aging and
shortens lifespan. HCMV is the most common 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 pivot points in the viral transcription-DNA replication cycle that are
vulnerable new targets for therapeutic intervention. This proposal is based on the premise that our gap in
knowledge of how viral early transcription begets viral DNA replication and viral DNA replication begets viral
late transcription limits our ability to design therapeutic treatments for the viral disease. We have developed
modified PRO-Seq and PRO-Cap methods to determine exactly where on the viral genome that Pol II and
its attached nascent transcript is located and at what frequency the engaged Pol II is at that nucleotide
position during the infection. This allows us to precisely determine where transcription is initiating, the extent
of promoter-proximal Pol II pausing, and the degree to which productive transcription elongation is taking
place. We designed bioinformatics algorithms to analyze this data. Our preliminary studies show that HCMV
utilizes host Pol II elongation control in early and late infection, but HCMV evolved different strategies in
promoting the viral transcription and linking it to viral DNA replication. Frequently used viral promoters more
often contain upstream TATA elements than do host promoters and viral initiator elements differ from that of
the host in nucleotide preference. In late infection, HCMV and not the host uses TATT as a Pol II positioning
element, which presumably requires the actions of viral late transcription factors (LTFs). We also find that
nearly 20% of paused Pol II is found in the non-coding long RNA4.9 gene at a location in the viral lytic origin
of replication (oriLyt) that is essential for oriLyt function; robust enhancer transcription underlies the world
renown viral major immediate-early promoter; and viral transcription is pervasive and exhibits a pattern
predictive of that arising from an unchromatinzed DNA template. Our research plan is designed to further
validate, establish meaning of, and mechanistically understand these findings. To advance these objectives,
we have adapted a newly developed approach to specifically and rapidly deplete viral proteins putatively
involved in viral transcription. As proof of concept, we observe changes in levels of multiple viral RNAs after
eliminating all the viral IE2 protein isoforms in late infection over a 6-hr timeframe, suggesting that the
actions of one or more of these viral protein isoforms may have an overarching effect on viral...

## Key facts

- **NIH application ID:** 10047701
- **Project number:** 5I01BX004434-03
- **Recipient organization:** IOWA CITY VA MEDICAL CENTER
- **Principal Investigator:** JEFFERY L MEIER
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-10-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10047701

## Citation

> US National Institutes of Health, RePORTER application 10047701, Mechanisms regulating cytomegalovirus (5I01BX004434-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10047701. Licensed CC0.

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