# HCMV regulation of monocyte/macrophage host cell signaling in viral reactivation

> **NIH NIH P01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $375,182

## Abstract

SUMMARY – PROJECT 5
 Human cytomegalovirus (HCMV) is a significant cause of morbidity and mortality after hematopoietic
stem cell transplant (HSCT) and solid organ transplant (SOT) due to reactivation or a new infection in these
transplant recipients. Our combined PPG laboratories have shown that HCMV infection of CD34+ hematopoietic
progenitor cells (HPCs) the site of HCMV latency and subsequent reactivation alters hematopoietic events to
favor HPC differentiation towards the myeloid lineage. To fully understand HCMV reactivation process, we need
not only understand the process of how reactivating virus in CD34+ HPC directs differentiation towards the
myeloid lineage, but also mechanistically how HCMV reactivation in monocytes directs signaling to
promote differentiation towards productive macrophages.
 Through our collaborative program, we have identified viral genes (e.g., UL135, US28, UL7/8) and
miRNAs (e.g. miR-US22) that are required for reactivation. Furthermore, through the use of deletion mutant
viruses that fail to reactivate, we have identified the existence of blockades to HCMV reactivation that are
associated with differentiation into macrophages. The signaling events important for reactivation of latent virus
in tissue macrophages remains poorly understood. We suggest temporally unique roles for UL135, US28
and UL7/8 and a unique intersection of these gene products with HCMV miRNAs expressed during
latency in usurping the signaling necessary to promote reactivation in this essential cell type. We
hypothesize distinct signaling events in monocyte to macrophage differentiation relieve blockades to reactivation
and these reactivation events are specifically driven by modifications to cellular signaling by the combined effort
of these viral factors. To test our hypothesis, we propose the following aims. Specific Aim 1. Defining signaling
networks for HCMV latency and reactivation in monocytes and macrophages. We hypothesize that functionally
distinct host cell responses in monocyte-to-macrophage differentiation are essential for reactivation. Specific
Aim 2. Determine checkpoint blockades for viruses that fail to reactivate. We hypothesize that a failure in specific
cellular signaling reprogramming during reactivation will result in a cell that phenotypically is unable to support
viral replication. Specific Aim 3. Define the signaling nodes modulated by infection for reactivation in
monocytes/macrophages. We hypothesize that the EGFR and RhoA signaling pathways are critical for HCMV
latency and reactivation in macrophages.
 IMPACT: These proposed aims will allow us to gain greater insight and as we integrate our collective
work, we hope to translate the results into novel molecular signatures designed to improve the outcome of an
infection that remains a significant problem in transplant recipients.

## Key facts

- **NIH application ID:** 10899436
- **Project number:** 5P01AI127335-08
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** ANDREW D YUROCHKO
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $375,182
- **Award type:** 5
- **Project period:** 2017-08-15 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10899436

## Citation

> US National Institutes of Health, RePORTER application 10899436, HCMV regulation of monocyte/macrophage host cell signaling in viral reactivation (5P01AI127335-08). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10899436. Licensed CC0.

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