# HCMV UL7 regulation of host cell signaling in viral latency and hematopoiesis

> **NIH NIH P01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $246,190

## Abstract

PROJECT 4: SUMMARY
Human cytomegalovirus (HCMV) is a -herpesvirus infecting 44-100% of the population and remains a
significant cause of morbidity and mortality in solid organ transplant (SOT) and allogeneic hematopoietic stem
cell transplant (SCT) recipients. Infection in SCT patients is often associated with myelosuppression and graft
failure due to virus reactivation from latency but the associated mechanisms are still largely unknown. We have
recently identified a secreted viral factor, UL7, containing an Ig-like domain with structural and functional
homology to carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), a protein with multiple
cellular activities including differentiation. We recently demonstrated that UL7 stimulates an inflammatory
response in endothelial cells, inducing the secretion of IL-6 and other cytokines mediated in part through the
phosphorylation of STAT3 and ERK1/2 in the JAK/STAT and MAP kinase pathways. Secretion of IL-6 and
activation of the ERK-MAPK signaling pathway have been reported to stimulate viral reactivation. Importantly,
we have shown that although UL7 is not expressed during latency, HCMV with a deletion of UL7 fails to
reactivate in latently infected CD34+ HPCs in vitro and in vivo although the virus is replication competent in
fibroblasts. These data indicate that UL7 is acting after the initiation of reactivation in latently infected CD34+
HPCs but before the lytic program is initiated, suggesting that UL7 reprogramming of the cell is essential for
the reactivation event. In addition, we have shown that UL7 is sufficient to promote CD34+ HPC differentiation
into myeloid lineage cells. Therefore, based upon our exciting new findings, we hypothesize that UL7
modulates the JAK-STAT-AKT pathways downstream of the Epidermal Growth Factor Receptor (EGFR) to
promote reactivation from latency and cellular differentiation for viral dissemination. In this project we will
examine UL7 signaling in CD34+ HPCs and identify the cellular pathways necessary for viral reactivation and
hematopoiesis in the context of infection. We will also determine whether these UL7 pathways cross-talk with
pathways modulated by US28 (Project 3) and UL133/8 (Project 1) or HCMV miRNAs (Project 2), other HCMV
factors important to latency and differentiation that modulate host signaling downstream of EGFR (Project 5).
We propose the following specific aims: 1) To determine how UL7 signaling in CD34+ HPCs intersects with
EGFR signaling pathways using a multi-omics approach; 2) To determine what molecular characteristics of
UL7 mediate HCMV latency and reactivation using both in vitro CD34+ HPCs and in vivo humanized BLT
mouse model; 3) To determine what UL7 signaling pathways promote CD34+ HPC hematopoiesis also using
both in vitro CD34+ HPC and in vivo huBLT models. Results of this study will generate new virus latency and
reactivation paradigms promoting the development of novel therapies to prevent virus reactivation an...

## Key facts

- **NIH application ID:** 10216637
- **Project number:** 5P01AI127335-05
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Patrizia Caposio
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $246,190
- **Award type:** 5
- **Project period:** 2017-08-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10216637

## Citation

> US National Institutes of Health, RePORTER application 10216637, HCMV UL7 regulation of host cell signaling in viral latency and hematopoiesis (5P01AI127335-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10216637. Licensed CC0.

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