Wednesday, October 1, 2025 10/1/2025

Human Cytomegalovirus dysregulation of host hematopoietic progenitor cell signaling pathways to modulate latency and reactivation

Award Number: P01AI127335
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2017
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Human Cytomegalovirus dysregulation of host hematopoietic progenitor cell signaling pathways to modulate latency and reactivation - SUMMARY - OVERALL Human Cytomegalovirus (HCMV) is a significant cause of morbidity and mortality in hematopoietic stem cell transplant (HSCT) patients who often exhibit myelosuppression associated with virus infection. CD34+ Hematopoietic Progenitor Cells (HPCs) are a critical reservoir of latent HCMV that upon cytokine and growth factor signals differentiate into monocytes that further differentiate into macrophages activating production of infectious virus in tissues. Epidermal Growth Factor Receptor (EGFR) signaling pathways in CD34+ HPCs are critical not only for determining HCMV latency and reactivation but also for regulating progenitor cell homeostasis and hematopoiesis. Over the past 3.5 years we have identified critical EGFR signaling pathways regulated by UL138, UL136, UL135, US28, UL7, UL8, and multiple HCMV miRNAs that are important to maintain latency or induce viral reactivation. Most of these pathways are integrally linked with CD34+ HPC proliferation for maintenance of the progenitor cell in the bone marrow niche as well as myelopoiesis. We have shown that multiple HCMV miRNAs synergistically or antagonistically work together with HCMV proteins to regulate these signaling pathways necessary for latency or viral reactivation. In addition, we have observed that UL138 is associated with proteins involved in STAT1 signaling and that HCMV miRNAs target some of these factors. We hypothesize that UL138-WDR48-USP1 and -USP12 interactions along with US28 and the HCMV miRNAs regulate a STAT1 and AKT response to suppress virus replication for latency. We have also shown that US28 signaling induced by chemokines regulate latency or reactivation and is ligand specific. Additionally, we have observed that US28 activation of RhoA is highly regulated by HCMV miRNAs as well as UL8 signaling through the non-canonical Wnt pathway. We hypothesize that MEK/ERK signaling is essential to maintain latency while activation of the RhoA pathway is necessary for reactivation. While the current HCMV PPG has focused on identification of UL138, UL136, UL135, US28, UL7, and viral miRNA EGFR signaling targets, the proposed renewal will focus on how the different HCMV genes interact with one another to regulate these pathways and how they control the virus life cycle. 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 reactivation; Project 2: miRNA regulation of host cell signaling in viral latency and reactivation; Project 3: US28 regulation of host cell signaling in viral latency and reactivation; Project 4: UL7-8 regulation of host cell signaling in viral latency and reactivation; Project 5: HCMV regulation of monocyte/macrophage host cell signaling in viral reactivation), two scientific cores (Humanized Mouse Core; Biostatistics and Bioinformatics Core) to service these projects, and an Administrative Core to oversee and coordinate the entire program.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $2,545,712 )
2025	2025	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Allergy and Infectious Diseases Research	001	9	8/8/2025	NON-COMPETING CONTINUATION	$2,545,712
2025	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Allergy and Infectious Diseases Research	000	8	3/12/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,545,712

Issue Date FY: 2024 ( Subtotal = $2,562,331 )
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Allergy and Infectious Diseases Research	001	8	8/16/2024	NON-COMPETING CONTINUATION	$2,562,331
2024	2023	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Allergy and Infectious Diseases Research	000	7	2/15/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,562,331

Issue Date FY: 2023 ( Subtotal = $2,570,795 )
2023	2023	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Allergy and Infectious Diseases Research	002	7	8/4/2023	NON-COMPETING CONTINUATION	$2,570,795
2023	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Allergy and Infectious Diseases Research	001	6	2/17/2023	COMPETING CONTINUATION	$518,107
2023	2021	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Allergy and Infectious Diseases Research	000	5	2/17/2023	NON-COMPETING CONTINUATION	-$518,107
														Subtotal = $2,570,795

Issue Date FY: 2022 ( Subtotal = $2,605,842 )
2022	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Allergy and Infectious Diseases Research	000	6	5/26/2022	COMPETING CONTINUATION	$2,605,842
														Subtotal = $2,605,842

Issue Date FY: 2021 ( Subtotal = $1,808,089 )
2021	2021	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Allergy and Infectious Diseases Research	000	5	8/19/2021	NON-COMPETING CONTINUATION	$1,808,089
														Subtotal = $1,808,089

Issue Date FY: 2020 ( Subtotal = $1,814,596 )
2020	2020	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Allergy and Infectious Diseases Research	000	4	7/14/2020	NON-COMPETING CONTINUATION	$1,814,596
														Subtotal = $1,814,596

Issue Date FY: 2019 ( Subtotal = $1,820,785 )
2019	2019	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Allergy and Infectious Diseases Research	000	3	7/18/2019	NON-COMPETING CONTINUATION	$1,820,785
														Subtotal = $1,820,785

Issue Date FY: 2018 ( Subtotal = $1,823,847 )
2018	2018	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Allergy and Infectious Diseases Research	000	2	8/1/2018	NON-COMPETING CONTINUATION	$1,823,847
														Subtotal = $1,823,847

Issue Date FY: 2017 ( Subtotal = $2,000,000 )
2017	2017	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Allergy and Infectious Diseases Research	000	1	8/14/2017	NEW	$2,000,000
														Subtotal = $2,000,000

Grand Total All Awards = $19,551,997

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Human Cytomegalovirus dysregulation of host hematopoietic progenitor cell signaling pathways to modulate latency and reactivation

Award Number: P01AI127335

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/15/2017

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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