Monday, June 30, 2025 6/30/2025

Modulation of BRD4 to epigenetically suppress HIV

Award Number: R01AI157852
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: 06/17/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Modulation of BRD4 to epigenetically suppress HIV - ABSTRACT Integration of HIV viral DNA into host cell genomes and establishment of stable latent infection have posed a major obstacle for finding an HIV cure. HIV proviral expression in cell reservoirs is regulated by host epigenetic and transcriptional mechanisms. Identification of effective approaches targeting host machineries to disrupt or enforce HIV latency is a significant goal. BRD4 is an epigenetic reader that belongs to the bromodomain (BD) and extra-terminal domain (ET) protein family (BET). Via the BDs, BRD4 binds to acetyl-lysine (KAc) residues in chromatin histones and serves as a scaffolding platform for recruiting partner proteins through protein-protein interactions (PPI) to regulate gene transcription, including HIV. Modulation of BET/BRD4 by a pan-BET inhibitor (JQ1), which targets the classic KAc binding site in BDs, has been shown to activate HIV transcription. Recent studies by my group and others indicate that BRD4 is functionally versatile, and its activity on gene transcription is tailored by specific partner proteins it engages. Using structure-aided design, our studies (1, 2) have identified a lead small molecule (ZL0580) and several analogs that are distinct from JQ1 but induce HIV transcriptional suppression through BRD4. We demonstrate that ZL0580 induces suppression of both transcriptionally active and latent HIV in multiple cell models, including J-Lat, CD4 T cells and myeloid cells/microglia. Docking analyses of binding modes and mechanistic investigations indicate that unlike JQ1, ZL0580 targets a distinct new region of BRD4 BD1 for binding [non-acetyl-lysine (KAc) site] and induces HIV transcriptional suppression by inhibiting Tat transactivation and by inducing a repressive chromatin structure at the HIV LTR. Based on these novel findings, our central hypothesis is that host BRD4 and its associated epigenetic machinery can be modulated to repress HIV, leading to enforced HIV latency. Other than ZL0580, our ongoing research has identified another analog (YL0255) that is structurally close to ZL0580 and induces stronger HIV suppression. In this application, we will use ZL0580 and YL0255 as two novel molecular probes to systemically investigate modulation of BRD4 in HIV epigenetic suppression. In Aim 1, we will determine if BRD4 is a selective protein target for ZL0580/YL0255 and the underlying structural basis. In Aim 2, we will elucidate the molecular mechanisms by which modulation of BRD4 by ZL0580/YL0255 induces HIV epigenetic suppression. In Aim 3, as a proof of concept, we will examine if modulation of BRD4 by ZL0580/YL0255 induces repression of latent HIV in vivo. Collectively, these studies are critical for better understanding HIV epigenetic regulation and latency and will lay critical groundwork for developing novel strategies for inducing HIV suppression and/or silencing in future.


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 = $902,028 )
2025	2025	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	001	5	6/19/2025	EXTENSION WITH OR WITHOUT FUNDS	$902,028
2025	2024	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	000	4	6/19/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $902,028

Issue Date FY: 2024 ( Subtotal = $601,727 )
2024	2024	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	000	4	5/21/2024	NON-COMPETING CONTINUATION	$601,727
														Subtotal = $601,727

Issue Date FY: 2023 ( Subtotal = $301,426 )
2023	2023	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	000	3	6/19/2023	NON-COMPETING CONTINUATION	$301,426
														Subtotal = $301,426

Issue Date FY: 2022 ( Subtotal = $601,727 )
2022	2022	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	000	2	5/19/2022	NON-COMPETING CONTINUATION	$601,727
														Subtotal = $601,727

Issue Date FY: 2021 ( Subtotal = $601,727 )
2021	2021	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	000	1	6/17/2021	NEW	$601,727
														Subtotal = $601,727

Grand Total All Awards = $3,008,635

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Modulation of BRD4 to epigenetically suppress HIV

Award Number: R01AI157852

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: 06/17/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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