Tuesday, July 1, 2025 7/1/2025

Virus-host interactions regulating innate signaling for human cytomegalovirus latency

Award Number: R01AI169728
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: 07/01/2025
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Virus-host interactions regulating innate signaling for human cytomegalovirus latency - PROJECT SUMMARY The goal of our research program is to elucidate molecular mechanisms by which HCMV regulates host signaling in CD34+ hematopoietic progenitor cells (HPCs) for the establishment and maintenance of viral latency and reactivation from latency. HCMV remains a significant cause of morbidity and mortality after solid organ and hematopoietic stem cell transplantation despite advances in diagnostics and therapeutics. HCMV latency is complex and the signaling mechanisms regulating the establishment and maintenance of HCMV latency, as well as for reactivation of HCMV, are poorly understood. We have identified a locus of viral genes in the ULb’ region of the genome that coordinates the expression of four genes, UL133, UL135, UL136, and UL138, from polycistronic transcripts. Using state-of-the art in vitro models in human CD34+ HPCs and in vivo models in humanized mice, we will define virus-host interactions modulating host signaling for the establishment of latency. Our preliminary data show that the latency determinant, UL138, interacts with host WD Repeat containing protein 48 (WDR48), which serves as a scaffold to activate ubiquitin specific protease, USP1, USP12, and USP46. WDR48-USP1 complexes regulate STAT1 and AKT signaling and we demonstrate that UL138 directs the activity of WDR48-USP1 to induce the activation of STAT1. We further show that USP1 activity it important for the establishment of a latent infection, such that when USP1 is inhibited, the virus replicates in the absence of a replication stimulus. We hypothesize that UL138 interaction directs WDR48-USP complexes to regulate innate signaling to suppress virus replication to prevent reactivation. In Aim 1, we will determine how UL138 impacts WDR48/USP complexes and function. We will map the amino acids in UL138 that are required for interaction with WDR48/USP complexes and generate recombinant viruses defective for these interactions. We will distinguish roles of the UL138-WDR48/USP1 interactions from that of UL138-EGFR interactions. Further, we have shown that UL138 sustains AKT signaling, at least in part through an interaction with EGFR, but interaction with USP12 and USP46 may provide additional avenues to the regulation of AKT. Aim 2 will determine how UL138-WDR48/USP interactions impact latency and reactivation and the role of UL138 in activating STAT1 and AKT using recombinant viruses and knockdown of host factors. This project will provide the comprehensive and mechanistic insights into the multi-faceted regulation of host signaling for the control of HCMV latency. The network of viral and host factors we have identified uniquely position us to define novel host and viral targets for antiviral strategies to control HCMV latency or reactivation.


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 = $388,312 )
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Allergy and Infectious Diseases Research	001	4	6/23/2025	NON-COMPETING CONTINUATION	-$364,323
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Allergy and Infectious Diseases Research	000	4	2/12/2025	NON-COMPETING CONTINUATION	$364,324
2025	2025	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	002	5	6/24/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$388,311
														Subtotal = $388,312

Issue Date FY: 2024 ( Subtotal = $389,819 )
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Allergy and Infectious Diseases Research	000	3	1/22/2024	NON-COMPETING CONTINUATION	$350,837
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Allergy and Infectious Diseases Research	001	3	5/23/2024	NON-COMPETING CONTINUATION	$38,982
														Subtotal = $389,819

Issue Date FY: 2023 ( Subtotal = $376,755 )
2023	2023	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Allergy and Infectious Diseases Research	000	2	1/26/2023	NON-COMPETING CONTINUATION	$376,755
														Subtotal = $376,755

Issue Date FY: 2022 ( Subtotal = $377,273 )
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Allergy and Infectious Diseases Research	000	1	2/7/2022	NEW	$377,273
														Subtotal = $377,273

Grand Total All Awards = $1,532,159

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Virus-host interactions regulating innate signaling for human cytomegalovirus latency

Award Number: R01AI169728

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: 07/01/2025

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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