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Roles of the UL148 glycoprotein in human cytomegalovirus infection

Award Number: R01AI116851
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: 12/15/2015
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Roles of the UL148 glycoprotein in human cytomegalovirus infection - This project focuses on the role of glycobiology in human cytomegalovirus (HCMV) immune evasion strategies. Our long-term goal is to understand how the virus exploits host protein glycosylation pathways to shield its virions and decorate the surfaces of infected cells with oligosaccharide patterns that prevent antibody binding and/or suppress immune responses. The Specific Aims are (1) to evaluate how the HCMV ER resident protein UL148 impacts the glycocalyx, or “sugar cloak,” of virions and infected cells, (2) to carry out a structure function analysis of UL148 to determine the mechanisms by which UL148 activates sculpts the host cell to enhance glycosylation of virion envelope proteins, and (3) to evaluate how UL148 contributes to evasion of antibody responses. Throughout the three Specific Aims, wild-type (WT) and UL148-null mutant viruses are evaluated in comparison to each other. In Specific Aim 1, mass spectrometry based ‘glycomics’ is applied to profile N-linked oligosaccharide structures conjugated to virion envelope proteins and surface proteins of infected cells in the presence versus absence of UL148. A second aspect of Aim 1 makes use of mass spectrometry-based proteomics together with genetic and pharmacological perturbations targeting the unfolded protein response (UPR) and cellular genes whose expression is positively regulated by UL148 to determine how the viral protein harnesses the host cell’s stress response circuitry toward the generation of virions that resist neutralization by antibodies. In Specific Aim 2, computational predictions of UL148’s three-dimensional protein structure are used to guide mutagenesis studies aimed at understanding the molecular basis for its biological functions, focusing in large part on the roles of (i) a consensus metal binding motif and (ii) two non- conserved cysteine residues. Aim 2 also leverages structural models non-human primate cytomegaloviruses homologs to elucidate the determinants of HCMV UL148’s unique biological functions. These studies will make use of recombinant HCMVs to test the impact of selected mutations and chimeric UL148 proteins in the context of infected cells. In Specific Aim 3, we will (i) characterize UL148’s impact on neutralization resistance of virions while targeting glycan modification enzymes hypothesized to be important for biogenesis of neutralization resistant virions, (ii) map specific antigenic domains on virion glycoproteins whose reactivity to neutralizing antibodies is impacted by UL148, (iii) compare the humoral immunogenicity of UL148 competent versus UL148-null HCMV virions in a mouse model, testing for neutralizing antibody titers, and overall polyclonal antibody titers against whole virions, viral envelope proteins and internal virion antigens. Collectively, these studies will address a key knowledge gap concerning how enveloped large DNA viruses exploit glycobiology to evade adaptive immunity and establish persistent infection.


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 = $0 )
2025	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	001	8	5/2/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$256,871
2025	2024	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Allergy and Infectious Diseases Research	000	7	5/2/2025	NON-COMPETING CONTINUATION	-$256,871
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $399,582 )
2024	2024	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Allergy and Infectious Diseases Research	002	7	6/21/2024	NON-COMPETING CONTINUATION	$399,582
2024	2023	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Allergy and Infectious Diseases Research	001	6	6/10/2024	COMPETING CONTINUATION	$5,752
2024	2020	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Allergy and Infectious Diseases Research	000	5	6/10/2024	NON-COMPETING CONTINUATION	-$5,752
														Subtotal = $399,582

Issue Date FY: 2023 ( Subtotal = $416,803 )
2023	2023	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Allergy and Infectious Diseases Research	000	6	7/14/2023	COMPETING CONTINUATION	$416,803
														Subtotal = $416,803

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Allergy and Infectious Diseases Research	000	5	11/16/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $362,500 )
2020	2020	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Allergy and Infectious Diseases Research	000	5	11/19/2019	NON-COMPETING CONTINUATION	$362,500
														Subtotal = $362,500

Issue Date FY: 2019 ( Subtotal = $362,500 )
2019	2019	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Allergy and Infectious Diseases Research	000	4	11/21/2018	NON-COMPETING CONTINUATION	$362,500
														Subtotal = $362,500

Issue Date FY: 2018 ( Subtotal = $362,500 )
2018	2018	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Allergy and Infectious Diseases Research	000	3	11/8/2017	NON-COMPETING CONTINUATION	$362,500
														Subtotal = $362,500

Issue Date FY: 2017 ( Subtotal = $362,500 )
2017	2017	LOUISIANA STATE UNIVERSITY SYSTEM	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Allergy and Infectious Diseases Research	000	2	11/10/2016	NON-COMPETING CONTINUATION	$362,500
														Subtotal = $362,500

Issue Date FY: 2016 ( Subtotal = $356,756 )
2016	2016	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER	POST OFFICE BOX 33932	SHREVEPORT	LA	71130	CADDO	USA	Allergy and Infectious Diseases Research	000	1	12/11/2015	NEW	$356,756
														Subtotal = $356,756

Grand Total All Awards = $2,623,141

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Roles of the UL148 glycoprotein in human cytomegalovirus infection

Award Number: R01AI116851

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: 12/15/2015

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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