Tuesday, November 4, 2025 11/4/2025

HOPE - HIV Obstruction by Programmed Epigenetics

Award Number: UM1AI164559
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/16/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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HOPE - HIV Obstruction by Programmed Epigenetics - PROJECT SUMMARY/ABSTACT After 40 years, a cure for people living with HIV (PLWH) remains both elusive and one of NIAID/NIH’s highest priorities. Rebound-competent latent reservoir cells persist despite antiretroviral therapy and rekindle infection due to the lack of efficient proviral silencing. The underlying hypothesis of the HIV Obstruction by Programmed Epigenetics (HOPE) Collaboratory application is a novel “block-lock-excise” approach—that entails the long-term durable silencing of viral expression towards permanent excision of the latent provirus—will lead to the permanent control of the virus in the absence of therapy. A graded transformation of remnant HIV in PLWH is proposed from latent into silent to permanently defective proviruses, thus emulating and accelerating the natural path that human endogenous retroviruses have taken in the human genome over millions of years. This hypothesis was formulated on the basis of 30+ years of dedicated research by HOPE investigators into the underlying mechanisms of HIV latency, lack of success to date with latency-reversing strategies, recent results with Tat inhibitor didehydro-Cortistatin A (dCA) and ELITE controllers showing that a successful ‘functional’ HIV cure could arise if there is a deep silencing of reservoir virus, and the availability of advanced genome- engineering technologies (Brec1 recombinase, peptide nucleic acids, CRISPR-base editors) for direct delivery of the final coup de grace: excision of remnant virus for permanent cure. The central hypothesis will be tested in three Research Focuses (RFs) and five central objectives shared between the three RFs. Specific Aim (RF) 1: Define mechanistically the durable transcriptional silencing of HIV across all T- and myeloid cell subsets by combinatorial targeting of key host and viral factors. Specific Aim (RF) 2: Develop and characterize next- generation HIV silencing approaches in the control of HIV rebound. Specific Aim (RF) 3: Disable the silenced HIV-1 provirus by targeted genome engineering. Objective 1: Determine the epigenetic architecture of the integrated provirus at different integration sites that prevents permanent silencing of latent HIV. Objective 2: Define, at the molecular level, cell types and epigenetic cell states that favor viral rebound. Objective 3: Identify molecular functions of Tat and host factors that prevent permanent silencing. Objective 4: Learn from HERV silencing and mutational decay in the human genome. Objective 5: Respond to community expectations around ‘functional’ and ‘classical’ cure approaches. The HOPE Collaboratory partnered with the San Francisco AIDS Foundation to build a strong art-based community education program and with three primary industry leaders, Amgen, Sangamo and Constellation, who will provide intellectual and materialistic support. We also engaged with four clinical cohorts of PLWH for clinical sample analysis in the US, Brazil and Africa. Collectively, the innovative science, renowned members, collaborative organizational structure and milestone- driven research plan of the HOPE Collaboratory represents a new and substantive departure from the status quo and promises a fundamental new approach to HIV Cure strategies.


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 = $4,951,244 )
2025	2025	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	5	7/18/2025	NON-COMPETING CONTINUATION	$4,951,244
														Subtotal = $4,951,244

Issue Date FY: 2024 ( Subtotal = $5,336,026 )
2024	2024	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	4	5/6/2024	NON-COMPETING CONTINUATION	$5,336,026
														Subtotal = $5,336,026

Issue Date FY: 2023 ( Subtotal = $6,334,269 )
2023	2023	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	001	3	7/5/2023	NON-COMPETING CONTINUATION	$998,243
2023	2023	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	3	4/20/2023	NON-COMPETING CONTINUATION	$5,336,026
														Subtotal = $6,334,269

Issue Date FY: 2022 ( Subtotal = $5,336,026 )
2022	2022	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	001	2	5/20/2022	NON-COMPETING CONTINUATION	$5,336,026
2022	2021	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	1	5/5/2022	NEW	$0
														Subtotal = $5,336,026

Issue Date FY: 2021 ( Subtotal = $5,336,026 )
2021	2021	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	1	8/13/2021	NEW	$5,336,026
														Subtotal = $5,336,026

Grand Total All Awards = $27,293,591

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HOPE - HIV Obstruction by Programmed Epigenetics

Award Number: UM1AI164559

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/16/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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