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CMV responses in autoantibody positive subjects advocate antiviral treatments for prevention of T1D

Award Number: R01AI150274
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: 09/20/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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CMV responses in autoantibody positive subjects advocate antiviral treatments for prevention of T1D - Project Abstract While environmental entities instigate T1D development, their identity is unknown. Genetics greatly increases risk, but the discordance between identical twins proves an equally critical role for exogenous factors. To identify causal entities, sampling must occur before clinical disease develops. Although labor intensive and costly, prospective longitudinal testing is the only way to illuminate the mysterious events that precede disease. Results from our recent collaboration with the TrialNet Pathway to Prevention study point to a role for CMV infection in T1D development. We found a striking expansion of terminally-differentiated short lived effector CD8 T cells (SLEC) in seroconverted (AA+) at-risk subjects. The frequencies of SLEC are highest in seroconverted subjects that progress to disease. This SLEC subset is identical to the well-characterized CD8 response to CMV. Importantly, we found the SLEC expansion is strongly associated with CMV seropositivity. Our findings demonstrate that an expanded, exhausted antiviral response occurs one year before autoimmune T1D develops. We also determined that SLEC levels correlate strongly with IA-2 autoantibodies, demonstrating a connection between CMV and autoimmunity. T1D results from autoreactive CD8 T cell-mediated attack on pancreatic islets. These autoreactive T cells may arise as a byproduct of the anti- viral response. Our overarching hypothesis is that CMV is an important environmental factor accelerating T1D development in children with genetic risk. The objective of this application is to longitudinally probe the preclinical disease process and unravel the mechanisms connecting CMV and T1D. In Aim 1 we propose to derive kinetic measurements through a longitudinal study. We hypothesize that genetically susceptible pre-T1D children show increased levels of exhausted CD8 T cells prior to the development of autoantibodies and/or clinical autoimmunity. In aim 2 we will measure CMV replication and persistence in at risk subjects that develop autoimmunity. We hypothesize that the accumulation of exhausted CD8 T cells causes viral persistence. In aim 3 we will test mechanisms whereby the virus activates islet specific CD8 T cells. We hypothesize that CMV infection induces the expansion of islet antigen-specific CD8 T cells. An established connection between CMV replication and T1D will point to antiviral therapies as efficacious in subjects with high genetic risk. Furthermore, levels of CMV replication and SLEC represent interlocking biomarkers for stratifying subjects for antiviral and/or vaccine trials. Several CMV vaccines are currently being tested in the clinic. Our results will also facilitate the understanding of other CMV-related human diseases.


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: 2027 ( Subtotal = $0 )
2027	2024	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	4215 EMILE ST	OMAHA	NE	68105	DOUGLAS	USA	Allergy and Infectious Diseases Research	000	5	11/3/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	4215 EMILE ST	OMAHA	NE	68105	DOUGLAS	USA	Allergy and Infectious Diseases Research	000	5	9/12/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $727,790 )
2024	2024	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Allergy and Infectious Diseases Research	001	5	8/13/2024	NON-COMPETING CONTINUATION	$728,669
2024	2020	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Allergy and Infectious Diseases Research	000	2	5/24/2024	SUPPLEMENT FOR EXPANSION	-$879
														Subtotal = $727,790

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Allergy and Infectious Diseases Research	001	4	8/10/2023	NON-COMPETING CONTINUATION	$0
2023	2020	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Allergy and Infectious Diseases Research	000	2	1/6/2023	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $728,669 )
2022	2022	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Allergy and Infectious Diseases Research	001	4	8/23/2022	NON-COMPETING CONTINUATION	$728,669
2022	2020	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Allergy and Infectious Diseases Research	000	2	10/11/2021	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $728,669

Issue Date FY: 2021 ( Subtotal = $728,669 )
2021	2021	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Allergy and Infectious Diseases Research	000	3	8/12/2021	NON-COMPETING CONTINUATION	$728,669
														Subtotal = $728,669

Issue Date FY: 2020 ( Subtotal = $953,802 )
2020	2020	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Allergy and Infectious Diseases Research	002	2	8/19/2020	SUPPLEMENT FOR EXPANSION	$63,108
2020	2020	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Allergy and Infectious Diseases Research	001	2	8/14/2020	NON-COMPETING CONTINUATION	$733,450
2020	2020	UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Allergy and Infectious Diseases Research	000	1	5/19/2020	SUPPLEMENT FOR EXPANSION	$157,244
														Subtotal = $953,802

Issue Date FY: 2019 ( Subtotal = $724,605 )
2019	2019	UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Allergy and Infectious Diseases Research	000	1	9/20/2019	NEW	$724,605
														Subtotal = $724,605

Grand Total All Awards = $3,863,535

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CMV responses in autoantibody positive subjects advocate antiviral treatments for prevention of T1D

Award Number: R01AI150274

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: 09/20/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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