# Human Cytomegalovirus dysregulation of host hematopoietic progenitor cell signaling pathways to modulate latency, reactivation, and hematopoiesis during transplantation

> **NIH NIH P01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $1,808,089

## Abstract

OVERALL PROJECT SUMMARY/ABSTRACT
The goal of our program is to elucidate the molecular mechanisms of HCMV regulation of host signaling in the
establishment and maintenance of viral latency and reactivation, and determine how viral dysregulation of
CD34+ Hematopoietic Progenitor Cells (HPCs) signaling may compromise hematopoiesis. HCMV remains a
significant cause of morbidity and mortality after Solid Organ Transplantation (SOT) and Hematopoietic Stem
Cell Transplantation (HSCT), and myelosuppression is a common clinical manifestation of HCMV infection in
these patients. HPCs represent a critical reservoir of latent HCMV in the transplant recipient, thereby providing
a source of virus for dissemination to visceral organs.
Preliminary data from our group using an in vitro CD34+ HPC model and mice engrafted with human fetal bone
marrow, liver and thymus (huBLT mice) have shown that HCMV regulation of Epidermal Growth Factor
Receptor (EGFR) and downstream signaling in CD34+ HPCs is essential for viral latency and reactivation as
well as hematopoiesis. Our group has shown that multiple HCMV genes expressed in latently infected CD34+
HPCs including the UL133-138 locus, US28, UL7 and HCMV miRNAs target multiple signaling pathways
activated by EGFR to control viral latency/reactivation and hematopoiesis. We hypothesize that HCMV fine
tunes the activity of EGFR and its downstream pathways to balance states of viral latency and reactivation. We
also hypothesize that HCMV fine tunes signaling and cytokine secretion to impact hematopoiesis. Further, we
propose that this regulation meets antagonistic needs to promote dissemination but limit broad hematopoietic
differentiation to control reactivation.
This program project will test each of these hypotheses using the in vitro CD34+ HPC model in combination
with the huBLT mouse model and samples from SOT and HSCT patients. The complexity of signaling events
and approaches to comprehensively address questions on viral latency and hematopoiesis can only be
achieved through a collaborative effort under a PPG mechanism. Therefore we propose five highly integrated
research projects (Project 1: UL133/8 regulation of host cell signaling in viral latency and hematopoiesis;
Project 2: HCMV miRNA regulation of host cell signaling in viral latency and hematopoiesis; Project 3: HCMV
US28 regulation of host cell signaling in viral latency and hematopoiesis; Project 4: HCMV UL7 regulation of
host cell signaling in viral latency and hematopoiesis; Project 5: HCMV regulation of host cell signaling and
cytokines in myelosuppression), two scientific cores (Humanized Mouse Core; Genomics, Biostatistics and
Bioinformatics Core) to service these projects, and an Administrative Core to oversee and coordinate the entire
program.

## Key facts

- **NIH application ID:** 10216629
- **Project number:** 5P01AI127335-05
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** JAY A NELSON
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,808,089
- **Award type:** 5
- **Project period:** 2017-08-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10216629

## Citation

> US National Institutes of Health, RePORTER application 10216629, Human Cytomegalovirus dysregulation of host hematopoietic progenitor cell signaling pathways to modulate latency, reactivation, and hematopoiesis during transplantation (5P01AI127335-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10216629. Licensed CC0.

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