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Enhancing Susceptibility of HIV Reservoirs to CTL Through a Discovery to Translational Approach

Award Number: R01AI176601
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: 03/24/2023
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Enhancing Susceptibility of HIV Reservoirs to CTL Through a Discovery to Translational Approach - PROJECT SUMMARY/ABSTRACT Although modern antiretroviral (ARV) therapies have dramatically improved the outlooks for people living with HIV, they are unable to cure infection. For people with HIV a cure would represent freedom from many burdens, including stigma, expensive medications, and inflammation-associated co-morbidities. A cure would also have public health benefits, comprising a powerful tool to help end the HIV epidemic. Developing a cure for HIV requires developing an understanding of how the virus persists for years and decades in people, even when new rounds of cellular infection (replication) are blocked by ARVs, and despite the ongoing presence of antiviral immune responses. The dominant paradigm has been that the virus hides in a latent state in infected cells and is thus invisible to immune responses. Efforts to cure infection have therefore focused on therapeutically reversing HIV latency to expose these cells to elimination but have thus far yielded disappointing results. This, along with several converging lines of evidence, have led to more recent hypothesis that hiding from the immune system may not be the only mechanism by which HIV persists – but rather that these rare populations of infected cells may have been selected for those that possess cell-intrinsic resistance to killing by cytotoxic T-lymphocytes, even when they express antigen and are seen. This parallels recent findings from ImmunoOncology where it has now been well established that some immunogenic tumors undergo selection for cell-intrinsic resistance to CTL. For this project, we have assembled a team comprising a pioneer in establishing mechanisms of CTL resistance in tumors, and two HIV experts who have advanced the idea of CTL resistance in this setting through a series of ex vivo studies. By merging these areas of expertise, we Aim to comprehensively describe mechanisms of CTL resistance in HIV-infected primary CD4+ T-cells and to discern which of these are at play in real HIV reservoir cells from people with HIV. We will build from these results to select therapeutic targets and identify combination approaches that integrate these with HIV-specific CTL and latency reversal strategies to achieve specific elimination of HIV reservoir-harboring cells ex vivo. We will also leverage an innovative mouse model to test whether engaging these therapeutic targets limits the seeding of HIV reservoirs in vivo. The results of this project are thus expected to be: i) laying a broad foundation for understanding CTL resistance in the HIV reservoir and ii) pre-clinical validation of multiple therapeutic targets with the potential to contribute to a cure for HIV.


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 = $770,236 )
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Allergy and Infectious Diseases Research	000	3	2/13/2025	NON-COMPETING CONTINUATION	$770,236
														Subtotal = $770,236

Issue Date FY: 2024 ( Subtotal = $827,457 )
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Allergy and Infectious Diseases Research	001	2	5/23/2024	NON-COMPETING CONTINUATION	$82,747
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Allergy and Infectious Diseases Research	000	2	2/14/2024	NON-COMPETING CONTINUATION	$744,710
														Subtotal = $827,457

Issue Date FY: 2023 ( Subtotal = $862,207 )
2023	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	1	3/23/2023	NEW	$862,207
														Subtotal = $862,207

Grand Total All Awards = $2,459,900

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Enhancing Susceptibility of HIV Reservoirs to CTL Through a Discovery to Translational Approach

Award Number: R01AI176601

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: 03/24/2023

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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