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Dissecting immune surveillance to gammaherpesviruses

Award Number: R01AI155015
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: 09/16/2020
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Dissecting immune surveillance to gammaherpesviruses - A primary driver of immune deficiency caused by HIV is the destruction of T cells, which if left untreated results in AIDS. Depression of cellular immunity results in a failure to control pre-existing virus infections, such as those by the human gammaherpesviruses: the Epstein-Barr virus and the Kaposi's sarcoma-associated herpesvirus. In some AIDS patients this results in severe disease, due to a failure to control virus-infected cells. Disease is a consequence of infection of B cells that harbor latent infection in the absence of virus replication. Previous work has shown the memory CD8 T cell response is the most important component of immune surveillance that controls latently infected cells in healthy patients. Therefore deeper understanding of CD8 T cell-mediated immune surveillance can help us understand how this response fails in AIDS patients, promoting development of strategies to restore immune surveillance to prevent gammaherpesvirus-associated diseases. This proposal will build on the novel finding that the BTB-ZF family transcription repressor Zbtb20 is essential for effective immune surveillance against murine gammaherpesvirus-68 (MHV-68). This rodent virus has proven to be an excellent model for virus-immune interactions, recapitulating many of the immune mechanisms used to control AIDS-relevant gammaherpesviruses. Preliminary data show the absence of Zbtb20 prevents the generation of cells with an effector / effector memory transcriptional signature. In addition rates of both glycolytic and mitochondrial metabolism were aberrantly elevated in Zbtb20-deficient CD8 T cells, indicating an important role for Zbtb20 in regulating immunometabolic status appropriate for the differentiation state of the T cell. This is critical, as it is clear that the metabolic state of the T cell is a critical driver of differentiation to memory cells, but very little is known about the metabolic state required for long-term immune surveillance. Our transcriptomic data identify key genes in glycolytic and mitochondrial respiratory pathways that are elevated in the absence of Ztbtb20. We will test whether dysregulation of these genes leads to attrition of immune surveillance, and if gene knockdown restores appropriate T cell differentiation and immunometabolism. Further experiments test the extent to which Zbtb20 is necessary for protection from disease associated with gammaherpesvirus infection in mice lacking endogenous T cell immunity, to mimic AIDS-defining immunodeficiency. These parameters are also tested using T cells genetically modified to restore effector memory differentiation or normalize metabolic rates. In summary, the significance is a mechanistic understanding of what is required for effective immune surveillance against an important class of AIDS-associated pathogen. Armed with this knowledge, we can design improved immune-based therapies to prevent serious disease in AIDS patients.


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	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	5	10/19/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	5	7/22/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $582,013 )
2024	2024	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	5	8/16/2024	NON-COMPETING CONTINUATION	$582,013
														Subtotal = $582,013

Issue Date FY: 2023 ( Subtotal = $582,013 )
2023	2023	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	4	7/27/2023	NON-COMPETING CONTINUATION	$582,013
														Subtotal = $582,013

Issue Date FY: 2022 ( Subtotal = $582,013 )
2022	2022	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	3	8/18/2022	NON-COMPETING CONTINUATION	$582,013
														Subtotal = $582,013

Issue Date FY: 2021 ( Subtotal = $582,013 )
2021	2021	TRUSTEES OF DARTMOUTH COLLEGE	6001 PARKHURST HALL STE 207	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	2	8/11/2021	NON-COMPETING CONTINUATION	$582,013
														Subtotal = $582,013

Issue Date FY: 2020 ( Subtotal = $582,013 )
2020	2020	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	1	9/16/2020	NEW	$582,013
														Subtotal = $582,013

Grand Total All Awards = $2,910,065

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Dissecting immune surveillance to gammaherpesviruses

Award Number: R01AI155015

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: 09/16/2020

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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