Tuesday, November 4, 2025 11/4/2025

Role of Factor Acetylation in the Regulation of HIV Transcription

Award Number: R37AI083139
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: 07/01/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Role of Factor Acetylation in the Regulation of HIV Transcription - Fully exploiting the promise of factor acetylation as a relevant drug target in HIV infection has the potential to significantly advance progress towards effective functional cure strategies. The overall objective of this proposal is to define the unique role of factor acetylation in latency establishment, maintenance and reactivation. The central hypothesis is that acetyl-lysine readers proteins (BRD4 and RPRD1) are critical regulators of latent HIV infection. The short isoform of the BET protein BRD4 (sBET) and the BAF chromatin- remodeling complex silence transcription of HIV and endogenous retroviruses, consistent with the model that the complex senses and silences genome-invading retroviruses. RPRD1 proteins are a novel class of acetyl- lysine reader proteins that, without bromodomains, bind acetyl-lysine residues (K7ac) within the RNA polymerase II C-terminal domain, a mark that is found highly enriched at the latent HIV LTR. A model is proposed of a cascade of latency-establishing events during or shortly after proviral integration including the methyltransferase SMYD5, the KAT8 acetyltransferase (MOF complex) and the sBET/BAF complexes. To test this model, the following experiments are planned: Aim 1: To define the role of the sBET-BAF-KAT8- SMYD5 factors in genome surveillance. The working hypothesis is that a cascade of SMYD5, KAT8 and sBET/BAF activity senses double-stranded DNA breaks caused by integrating retroviruses and silences gene expression by positioning a repressive nucleosome at the transcription start site. Dual-fluorescent HIV, Cas9- induced DSBs and knockdown studies of sBET, KAT8 and SMYD5 will be used to test this hypothesis. Aim 2: To characterize recruitment of sBET-containing complexes to the integrated provirus. The working hypothesis is that a cascade of H3K36me3 and H4K16ac modifications recruits sBET-BAF to the integrating HIV promoter. Comprehensive mutagenesis, co-immunoprecipitation and ChIP experiments combined with factor knockdown are planned to test this hypothesis. Aim 3: To determine how RPRD1 proteins regulate HIV transcription via R-loops. The working hypothesis is that RPRD1 proteins read K7ac marks at the latent HIV promoter and prevent transcription elongation of the paused RNA polymerase through R-Loop formation (DNA-RNA hybrids). ChIP, DRIP (DNA-RNA IPs) and CRISPR-targeted nuclease recruitment to dissolve R- loops are planned to test this hypothesis. Important insights into the roles of H3K36me3, H4K16ac and R- loops in HIV latency establishment and maintenance are expected, enabling new cure therapies. RELEVANCE (See instructions): The proposed research is relevant to public health because it will determine if and how new acetyl-lysine reader proteins sBET and RPRD1 control HIV latency. These results will improve the understanding of the basic biology of HIV latency and will, ultimately, inform the development of new therapies to reverse HIV latency in infected individuals. This project supports the NIH’s mission and aligns with one of its high- priority topics of research that awards AIDS-designated funds to support research toward 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 = $737,100 )
2025	2025	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	002	16	6/23/2025	NON-COMPETING CONTINUATION	$737,100
2025	2024	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	001	15	2/25/2025	EXTENSION WITH OR WITHOUT FUNDS	$170,458
2025	2023	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	14	2/25/2025	NON-COMPETING CONTINUATION	-$170,458
														Subtotal = $737,100

Issue Date FY: 2024 ( Subtotal = $737,100 )
2024	2024	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	15	4/1/2024	EXTENSION WITH OR WITHOUT FUNDS	$737,100
														Subtotal = $737,100

Issue Date FY: 2023 ( Subtotal = $621,854 )
2023	2023	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	14	6/22/2023	NON-COMPETING CONTINUATION	$621,854
														Subtotal = $621,854

Issue Date FY: 2022 ( Subtotal = $635,719 )
2022	2022	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	001	13	7/13/2022	SUPPLEMENT FOR EXPANSION	$13,865
2022	2022	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	13	6/29/2022	NON-COMPETING CONTINUATION	$621,854
														Subtotal = $635,719

Issue Date FY: 2021 ( Subtotal = $750,731 )
2021	2021	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	12	6/29/2021	NON-COMPETING CONTINUATION	$621,854
2021	2021	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	001	12	9/2/2021	SUPPLEMENT FOR EXPANSION	$128,877
														Subtotal = $750,731

Issue Date FY: 2020 ( Subtotal = $691,945 )
2020	2020	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	001	11	7/1/2020	NON-COMPETING CONTINUATION	$621,854
2020	2019	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	10	3/23/2020	COMPETING CONTINUATION	$70,091
														Subtotal = $691,945

Issue Date FY: 2019 ( Subtotal = $621,854 )
2019	2019	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	10	7/15/2019	COMPETING CONTINUATION	$621,854
														Subtotal = $621,854

Grand Total All Awards = $4,796,303

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Role of Factor Acetylation in the Regulation of HIV Transcription

Award Number: R37AI083139

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: 07/01/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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