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Targeting PD-1 Pathway for Functional Cure of AIDS

Award Number: R01AI112787
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: 02/01/2014
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Targeting PD-1 Pathway for Functional Cure of AIDS - This proposal aims to develop an effective therapy to achieve HIV remission by improving the magnitude, breadth, and function of anti-viral CD8 T cells and reducing viral reservoirs using the SIV/macaque model. Dysfunctional anti-HIV immunity and the persistence of viral reservoirs represent two major issues that must be addressed by therapeutic approaches targeting functional cure for HIV. We believe that these two issues can be addressed effectively using a combination of vaccination and inhibiting the programmed death-1 co-inhibitory pathway (PD-1 blockade). Accordingly, during the past 9 years of this R37, we invested major efforts to comprehensively define the influence of the timing of PD-1 blockade at different stages of chronic SIV infection and during anti-retroviral therapy (ART) on restoring CD8 T cell function and diminishing viral reservoirs. We also tested the influence of combining PD-1 blockade with vaccination. These results showed that a combination of therapeutic vaccination under ART and PD-1 blockade post analytical treatment interruption (ATI) leads to a profound control of reemerging viremia with some animals suppressing viremia to below the level of detection for up to 24 weeks. These results demonstrated the utility of this combination approach towards achieving HIV remission. Our recent data in mice showed that the addition of IL-2 cytokine therapy to PD-1 blockade markedly enhances the induction of highly functional effector cells and modulates their differentiation program leading to better control of LCMV infection. Based on these exciting results, we propose to improve the therapeutic potential of PD-1 blockade by combining it with IL-2 cytokine therapy. We propose 3 specific aims. In Aim 1, we will determine the safety and therapeutic efficacy of a combination of PD-1 blockade and IL-2 cytokine therapy post ATI in SIV infected and vaccinated macaques. In Aim 2, we will define the heterogeneity of exhausted CD8 T cells during chronic SIV infection and define how PD-1 blockade with and without IL-2 will modify the T cell exhaustion program. In Aim 3, we will test if an improved therapeutic vaccine combined with PD-1 blockade plus IL-2 therapy can enhance control of reemerging SIV viremia. This will be a collaborative effort between Amara (Emory), Ahmed (Emory), and Freeman (Harvard) laboratories. All three labs have worked together for over 15 years to optimize the PD-1 blockade to treat chronic SIV infection. By the completion of these aims, we hope to develop potent immunotherapy to achieve profound and sustained control of SIV infection in the absence of ART therapy.


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: 2026 ( Subtotal = $907,904 )
2026	2026	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	13	12/30/2025	NON-COMPETING CONTINUATION	$907,904
														Subtotal = $907,904

Issue Date FY: 2025 ( Subtotal = $880,613 )
2025	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	12	11/27/2024	NON-COMPETING CONTINUATION	$880,613
														Subtotal = $880,613

Issue Date FY: 2024 ( Subtotal = $928,499 )
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	11	11/14/2023	COMPETING CONTINUATION	$837,698
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	001	11	8/22/2024	COMPETING CONTINUATION	$1
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	002	11	9/3/2024	COMPETING CONTINUATION	$90,800
														Subtotal = $928,499

Grand Total All Awards = $2,717,016

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Targeting PD-1 Pathway for Functional Cure of AIDS

Award Number: R01AI112787

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: 02/01/2014

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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