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Mechanisms of Human Cytomegalovirus Latency in Primary Human Hematopoietic Cells

Award Number: R37AI079059
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: 09/01/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Mechanisms of Human Cytomegalovirus Latency in Primary Human Hematopoietic Cells - PROJECT SUMMARY (See instructions): Human cytomegalovirus (HCMV) establishes a latent infection in hematopoietic progenitor cells (HPCs) and cells of the myeloid lineage and its reactivation is exquisitely linked to hematopoietic differentiation and stress. Latency is poorly defined for HCMV at the molecular and cellular level. The long-term goal of our work has been to define the mechanisms by which HCMV enters and exits the latent infection. The UL 133-UL 138 locus coordinates the expression of four genes, UL 133, UL 135, UL 136, and UL 138 with pro-latency and pro-reactivation functions. We have defined the cellular pathways modulated by these viral proteins to define mechanisms of latency and reactivation. Our work has shown that accumulation of the reactivation determinant, UL 136p33, is controlled by the host E3 ubiquitin ligase IDOL, which is induced by the liver X receptor in response to sterol levels. Maintenance of low levels of UL 136p33 by IDOL is critical for the establishment of latency and downregulation of IDOL with differentiation is important for reactivation. A host target of IDOL is the low-density lipoprotein receptor (LDLR). We determined that HCMV infection downregulates LDLR and prevents the maturation of LDLR through the ER. We show that UL 138 is important in driving ER-associated degradation (ERAD) of immature LDLR forms in infection. UL 138 further is required for the induction of the unfolded protein response and sterols in infection. We have identified UL 138-host interactors important to ERAD and regulation of the unfolded protein response and ER stress. We hypothesize that UL 138 regulates ER stress, proteostasis, and sterol metabolism important for viral latency through its ERAD-related host interactions. We will determine how UL 138 regulates ERAD by defining virus-host interactions (Aim 1), how UL 138-mediated regulation of ERAD impacts ER stress and lipogenesis/sterol synthesis in infection (Aim 2), and how this regulation of host pathways impacts the regulation of latency and reactivation (Aim 3). We anticipate that UL 138 regulation of ERAD impacts the cellular sterol environment sensed by HCMV to control UL 136p33 levels through changes in IDOL concentration for latency. Our work reveals new mechanisms by which HCMV controls UPR/ERAD with implications for the regulation of ER stress and sterol synthesis to regulate HCMV latency and reactivation. Defining these mechanisms elucidates novel host pathways important for HCMV latency and 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 = $402,424 )
2025	2025	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	002	18	8/18/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$402,424
2025	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Allergy and Infectious Diseases Research	003	17	9/17/2025	EXTENSION WITH OR WITHOUT FUNDS	$0
2025	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Allergy and Infectious Diseases Research	001	17	8/18/2025	EXTENSION WITH OR WITHOUT FUNDS	$0
2025	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Allergy and Infectious Diseases Research	000	16	4/3/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $402,424

Issue Date FY: 2024 ( Subtotal = $443,151 )
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Allergy and Infectious Diseases Research	000	17	6/21/2024	EXTENSION WITH OR WITHOUT FUNDS	$443,151
														Subtotal = $443,151

Issue Date FY: 2023 ( Subtotal = $375,390 )
2023	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Allergy and Infectious Diseases Research	000	16	8/11/2023	NON-COMPETING CONTINUATION	$375,390
														Subtotal = $375,390

Issue Date FY: 2022 ( Subtotal = $441,087 )
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Allergy and Infectious Diseases Research	001	15	8/24/2022	SUPPLEMENT FOR EXPANSION	$65,078
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Allergy and Infectious Diseases Research	000	15	8/23/2022	NON-COMPETING CONTINUATION	$376,009
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Allergy and Infectious Diseases Research	002	15	9/20/2022	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $441,087

Issue Date FY: 2021 ( Subtotal = $440,706 )
2021	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Allergy and Infectious Diseases Research	001	14	9/1/2021	SUPPLEMENT FOR EXPANSION	$64,123
2021	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Allergy and Infectious Diseases Research	000	14	8/11/2021	NON-COMPETING CONTINUATION	$376,583
														Subtotal = $440,706

Issue Date FY: 2020 ( Subtotal = $410,980 )
2020	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Allergy and Infectious Diseases Research	002	13	8/5/2020	NON-COMPETING CONTINUATION	$377,113
2020	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Allergy and Infectious Diseases Research	000	12	4/4/2020	COMPETING CONTINUATION	$33,867
2020	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Allergy and Infectious Diseases Research	001	12	7/31/2020	COMPETING CONTINUATION	$0
														Subtotal = $410,980

Grand Total All Awards = $2,513,738

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Mechanisms of Human Cytomegalovirus Latency in Primary Human Hematopoietic Cells

Award Number: R37AI079059

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: 09/01/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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