# HCMV miRNA regulation of host cell signaling in viral latency and reactivation

> **NIH NIH P01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $444,396

## Abstract

SUMMARY - PROJECT 2
Human cytomegalovirus (HCMV) reactivation from latency remains a serious complication under conditions of
immunosuppression. Latency and reactivation are complex processes regulated by a subset of viral proteins and
non-coding RNAs in CD34+ hematopoietic progenitor cells (HPCs). The goal of this project is to define how
HCMV microRNAs (miRNAs) refine and shape signaling mediated by viral proteins critical for the entry into and
exit from latency. We have previously determined that HCMV miRNAs interfere with multiple pathways in latently-
infected cells, including TGF, MEK/ERK and RhoA that have critical implications for HCMV latency. Importantly,
we have uncovered a role for HCMV miRNAs acting both in coordination and in opposition to viral proteins. For
example, in order to regulate apoptosis early after infection of CD34+ HPCs, miR-US5-1 and miR-UL112-3p act
in concert with UL7 (Project 4) to reduce the levels and activity of FOXO3a. In contrast, HCMV miR-US5-2 and
miR-US22 target components of the MEK/ERK signaling pathway downstream of EGFR critical for viral
reactivation and attenuate US28- and UL138-mediated signaling.
We have identified RhoA as a target of HCMV miR-US25-1 that plays a key role in regulating the proliferation of
latently-infected CD34+ HPCs through modulating cytokinesis. Intriguingly, HCMV US28 (Project 3) activates
RhoA through ligand-dependent signaling and recent proximity labelling experiments identified RhoGEFs and
Rho GTPases as components of the US28 signalosome. Mutation of US28 or chemical inhibition of RhoA
reduces viral reactivation, highlighting the importance of US28 and Rho signaling in the reactivation process.
Additionally, UL8 (Project 4) is essential for reactivation and activates Rho signaling through the Wnt pathway.
Moreover, proximity labelling experiments identified Wnt and Rho pathway components as part of the UL8
signalosome. We have identified additional HCMV miRNAs that target key components of the Wnt and Rho
GTPase pathways including the Wnt effector DVL2, RhoGEFs, the GTPase CDC42 and downstream effector
proteins, indicating that Rho GTPase signaling is intricately regulated by viral miRNAs in addition to being
stimulated by viral proteins. We hypothesize that HCMV miRNAs target components of the MEK/ERK pathway
to downregulate virus-mediated signaling at the time of reactivation, whereas miRNAs expressed during latency
target components of the Rho GTPase pathways to oppose the effects of virus-mediated signaling to maintain
the virus in latency.

## Key facts

- **NIH application ID:** 10899429
- **Project number:** 5P01AI127335-08
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** JAY A NELSON
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $444,396
- **Award type:** 5
- **Project period:** 2017-08-15 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10899429

## Citation

> US National Institutes of Health, RePORTER application 10899429, HCMV miRNA regulation of host cell signaling in viral latency and reactivation (5P01AI127335-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10899429. Licensed CC0.

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