Thursday, July 17, 2025 7/17/2025

Amplifying and Redirecting CMV-specific CD8 T cells to provide sustained control of HIV infection

Award Number: R01AI172607
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: 06/03/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Amplifying and Redirecting CMV-specific CD8 T cells to provide sustained control of HIV infection - The immune system of HIV-infected individuals is unable to eliminate latently infected cells following reactivation, resulting in the recurrence of viremia after stopping antiretroviral therapy, preventing functional cure. This necessitates lifelong ART for people with HIV (PWH). New strategies are needed to mobilize the immune system to prevent the emergence of HIV from the HIV reservoir after ART cessation. We recently developed synTacs, infusible immunostimulatory biologics consisting of dimeric Fc-domain scaffolds linking MHC molecules and virus-derived peptides (c-pMHC) capable of delivering antigen-specific TCR-signals and ligands that supply defined costimulatory signals. We demonstrated that synTacs bearing CMV-derived peptides, and anti-CD28 scFv or 4-1BBL signaling modules, stimulated vigorous and selective ex vivo and in vivo expansion of highly polyfunctional CMV-specific CD8+ T cells in PWH PBMC, which displayed potent in vivo anti-CMV activities. We also recently described the potent in vitro and in vivo anti-HIV activity of CAR-T cells that use a novel two- molecule duoCAR architecture to co-express two independent CARs, each recognizing a distinct gp120 epitope. HIV-specific T cell responses or CAR-T cell treatments fail to provide sustained control of HIV infection because of the eventual reduction or loss of their functional anti-HIV activity, even in the absence of mutational immune escape. In contrast, CMV-specific T cell responses consist of effector memory CD8 T cells that maintain their capacity for cytokine release, killing and proliferation and actually expand over time, a phenotype described as memory inflation. We hypothesize that combining the capacity of synTacs to activate and markedly expand CMV- specific CD8 T cells with novel strategies to redirect them to eliminate HIV-infected cells, would exploit the highly functional and resilient CMV-specific CD8 T cell responses to provide improved immune control of HIV infection. We propose to combine the capacity of synTacs to selectively activate and markedly expand CMV-specific CD8 T cells with potent and sustained anti-viral activity with three Specific Aims (SA) to redirect them to target HIV- infected cells. We will either convert the expanded CMV CD8 T cells into HIV-specific CAR T cells (SA 1), or anti-HIV T cells (SA 2), or modify the synTac structure to link CMV-c-pMHC, gp120-binders and costimulatory ligands, to both fully activate and direct CMV CD8 T cells to target HIV-infected cells (SA 3), thereby mobilizing an in vivo immune response that controls HIV infection, eliminates reactivated latently infected cells and provides sustained ART-free remission of HIV infection to PWH. Furthermore, we will also utilize synTacs delivering defined costimulatory signals, to extend our knowledge regarding the capacity of different costimulatory signals to generate the most potent CD8+ T cells and CAR-T cells for eliminating reactivated latently infected T cells.


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 = $1,679,994 )
2025	2025	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	002	4	6/3/2025	EXTENSION WITH OR WITHOUT FUNDS	$1,679,994
2025	2024	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	3	4/21/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2024	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	001	3	6/2/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,679,994

Issue Date FY: 2024 ( Subtotal = $939,292 )
2024	2024	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	3	5/17/2024	NON-COMPETING CONTINUATION	$839,997
2024	2024	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	001	3	5/20/2024	SUPPLEMENT FOR EXPANSION	$99,295
														Subtotal = $939,292

Issue Date FY: 2023 ( Subtotal = $958,641 )
2023	2023	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	001	2	6/7/2023	NON-COMPETING CONTINUATION	$839,997
2023	2023	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	1	4/18/2023	SUPPLEMENT FOR EXPANSION	$19,349
2023	2023	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	002	2	8/16/2023	SUPPLEMENT FOR EXPANSION	$99,295
														Subtotal = $958,641

Issue Date FY: 2022 ( Subtotal = $839,997 )
2022	2022	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	1	6/3/2022	NEW	$839,997
														Subtotal = $839,997

Grand Total All Awards = $4,417,924

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Amplifying and Redirecting CMV-specific CD8 T cells to provide sustained control of HIV infection

Award Number: R01AI172607

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: 06/03/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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