# Molecular Aspects of Cytomegalovirus Latency

> **NIH NIH R37** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $532,285

## Abstract

Project Summary:
The long-term goal of this project is to develop an understanding of the cellular and molecular mechanisms of
human cytomegalovirus (HCMV) latency in CD34+ hematopoietic progenitor cells (HPCs) and the effect of latent
and reactivating virus on hematopoiesis. The ability of HCMV to reactivate in CD34+ HPCs is exquisitely linked to
HPC differentiation and hematopoiesis. Understanding how HCMV regulates hematopoiesis is crucial to
identifying mechanisms of latency and reactivation as well as disease. HCMV is a species-specific virus that
establishes a persistent/latent infection in the host after primary infection. Our group and others have shown that
HCMV encodes several microRNAs (miRNAs), small 21-24 base pair single-stranded RNA species that regulate
gene expression and multiple cellular processes involved in the virus life-cycle. In preliminary work we have
observed that two HCMV latently expressed miRNAs up-regulate and one expressed during lytic replication
down-regulates Early Growth Response Gene-1 (Egr-1) that is a transcription factor induced by MEK/ERK
signaling that regulates the maintenance human progenitor cells (HPC) or “Stemness” in the bone marrow
through the induction and suppression of key cytokines and co-stimulatory molecules. Deletion of these two
HCMV miRNAs that up-regulate Egr-1 results in a virus that fails to reactivate in vitro or in a humanized mouse
model. Additionally, we have shown that the miRNAs that regulate Egr-1 signaling pathway alter HPC
myelopoiesis suggesting link between HPC latency and reactivation and HPC myelopoiesis. We also observe that
Egr-1 up-regulates UL138 expression a gene shown to maintain HCMV latency. Lastly, we show that HCMV
latent infection of HPC up-regulates expression of TGF-β that is regulated by Egr-1. Latent HCMV infection of
HPC inhibits myelopoiesis in vitro that is restored by neutralization of TGF-β. We hypothesize that HCMV miRNAs
that up-regulate Egr-1 maintain CD34+ HPC stemness and latency through expression of UL138 and miRNAs that
down-regulate Egr-1 induce reactivation thus providing a regulatory switch for viral latency or reactivation. In the
first aim we will identify and characterize additional HCMV miRNA signaling targets that regulate Egr-1 and their
role in viral latency and reactivation. In the second aim we will characterize HCMV miRNA regulation of Egr-1
mediated UL136 and UL138 expression in latency. In the last aim we will characterize HCMV miRNA regulation of
Egr-1 and TGF-β on HPC stemness and myelopoiesis using both in vitro systems and a unique humanized
mouse model. These studies have significant implications on HCMV induced myelosupression observed in bone
marrow transplant patients.

## Key facts

- **NIH application ID:** 9854866
- **Project number:** 5R37AI021640-35
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** JAY A NELSON
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $532,285
- **Award type:** 5
- **Project period:** 1984-12-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9854866

## Citation

> US National Institutes of Health, RePORTER application 9854866, Molecular Aspects of Cytomegalovirus Latency (5R37AI021640-35). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9854866. Licensed CC0.

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