# HCMV UL133/8 regulation of host cell signaling in viral latency and hematopoiesis

> **NIH NIH P01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $219,937

## Abstract

PROJECT SUMMARY
The goal of our Program is to elucidate the molecular mechanisms by which HCMV regulates host signaling in
CD34+ hematopoietic progenitor cells (HPCs) for the establishment and maintenance of viral latency and
reactivation, and to determine how viral dysregulation of signaling contributes to HCMV myelosuppression.
HCMV remains a significant cause of morbidity and mortality via myelosuppression after solid organ and
hematopoietic stem cell transplantation despite advances in diagnostics and therapeutics. HCMV latency is
complex and the signaling mechanisms for establishment and maintenance of HCMV latency, as well as for
reactivation of virus are poorly understood. Our program has identified a number of viral proteins and miRNAs
that regulate both latency and hematopoiesis by targeting epidermal growth factor receptor (EGFR) and
signaling pathways downstream of EGFR. The complexity of signaling events and approaches to
comprehensively address questions on viral latency and hematopoiesis can only be achieved through a
collaborative effort. Using state-of-the art in vitro models in primary, human CD34+ HPCs and in vivo models in
mice humanized with bone marrow, liver and thymus, our Program will address the individual and combined
roles of viral factors modulating host signaling. Our Project (Project 1) will address the roles of proteins
encoded within the UL133/8 “latency locus” in modulating host signaling. We have defined roles for the four
genes encoded by the UL133/8 locus in either positively or negatively regulating the maintenance of viral
latency. Intriguingly, these genes opposingly regulate the trafficking and activation of EGFR. We have shown
that EGFR and downstream PI3K signaling is important for the maintenance of latency and inhibitors of EGFR
or PI3K stimulate reactivation and replication. We hypothesize that EGFR is a critical signaling axis targeted by
UL133/8 proteins to modulate viral latency, reactivation and hematopoiesis. In Aim 1, we will use a systems
approach to define the global pathways regulated by UL133/8 proteins in the context of infection in CD34+
HPCs. We will then define the significance of UL133/8-modulation of host signaling to viral latency and
reactivation in Aim 2 and to hematopoiesis in Aim 3. Throughout our studies we will integrate our data sets with
those of the other Projects to determine how UL133/8 interfaces with other viral proteins (US28 in Project 3;
UL7 in Project 4) and viral miRNAs (Project 2) and contributes to the broader regulation of host signaling in
regulating latency, reactivation and hematopoiesis. Project 5, focused on defining the hematopoieitic signaling
pathways targeted by HCMV, will inform our understanding of pathways targeted by UL133/8 proteins to
regulate hematopoiesis. Collectively, our projects will provide the first comprehensive and mechanistic insights
into the multi-faceted regulation of host signaling for the control of HCMV latency and myelosuppression. ...

## Key facts

- **NIH application ID:** 10216633
- **Project number:** 5P01AI127335-05
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Felicia D Goodrum
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $219,937
- **Award type:** 5
- **Project period:** 2017-08-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10216633

## Citation

> US National Institutes of Health, RePORTER application 10216633, HCMV UL133/8 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/10216633. Licensed CC0.

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