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Blocking granzyme-mediated immune suppression to enhance HIV vaccine efficacy

Award Number: R01AI176519
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: 03/13/2023
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Blocking granzyme-mediated immune suppression to enhance HIV vaccine efficacy - SUMMARY Immunization represents one of the most successful public health interventions in human history, preventing more than 2 million deaths each year. Vaccine success depends on a variable combination of antibodies that can neutralize the invading pathogen and virus-specific T cells that kill infected targets. However, the induction of neutralizing antibodies and antiviral T cells that are sufficiently functional and broadly targeted to thwart a highly mutable pathogen like HIV has proven exceptionally difficult in both humans and animal models. Thus, there is currently no efficacious vaccine to prevent the nearly 5,000 new infections with HIV that occur each day. This shortcoming in vaccine success is likely due to intrinsic immune regulatory mechanisms that limit the quantity and quality of HIV-specific immune responses. Development of translational means to overcome these immunological roadblocks holds great promise for advancement of next-generation vaccines to prevent HIV infection and improve global health. Our research focuses on the remarkable capacity of natural killer (NK) cells to suppress the magnitude and quality of antiviral T and B cell responses triggered after immunization. NK cells impair the generation of protective neutralizing antibody responses by inhibiting follicular helper T cell responses and restricting affinity maturation of antibodies within germinal centers. This NK-cell immunosuppression also limits the quantity and quality of antiviral memory T cell responses. NK cells achieve this suppressive effect via perforin-dependent killing of activated T cells, although the specific receptors used to recognize target T cells and perforin-delivered granzymes involved in triggering cell death remain incompletely defined. Whereas inhibition of perforin could curtail NK cell-mediated immune suppression, this broad of an approach could temporarily undermine immunity against pathogens and tumors, and thus a more refined approach targeting granzymes is proposed. Therefore, the goal of this proposal is to advance an innovative high risk, high impact approach to foster HIV vaccine efficacy through selective inhibition of granzymes involved in the immunosuppressive activity of NK cells. Initial experiments in mice will use small molecule inhibitors and CRISPR to define the utility of targeting a specific granzyme to limit NK-cell killing of T cells and suppression of vaccine-elicited adaptive immunity. Select inhibitors will be validated in Rhesus macaques. Based on quantitatively defined go/no-go criteria establishing the success of granzyme targeting to enhance vaccine efficacy, we will proceed to evaluation of this approach in vaccine- mediated prevention of SIV infection in non-human primates. These experiments will also open impactful avenues of investigation into the molecular features of both the immunosuppressive subset of NK cells and targeted subpopulation of T cells. Thus, the proposed work will facilitate subsequent development and deployment of innovative strategies to enhance HIV vaccine efficacy.


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 = $556,715 )
2025	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Allergy and Infectious Diseases Research	000	3	4/21/2025	NON-COMPETING CONTINUATION	$556,715
														Subtotal = $556,715

Issue Date FY: 2024 ( Subtotal = $833,010 )
2024	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Allergy and Infectious Diseases Research	000	2	1/23/2024	NON-COMPETING CONTINUATION	$749,709
2024	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Allergy and Infectious Diseases Research	001	2	5/23/2024	NON-COMPETING CONTINUATION	$83,301
														Subtotal = $833,010

Issue Date FY: 2023 ( Subtotal = $851,001 )
2023	2023	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Allergy and Infectious Diseases Research	000	1	3/14/2023	NEW	$851,001
														Subtotal = $851,001

Grand Total All Awards = $2,240,726

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Blocking granzyme-mediated immune suppression to enhance HIV vaccine efficacy

Award Number: R01AI176519

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: 03/13/2023

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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