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HIV Activation by Targeted BRD4 Recruitment

Award Number: R21AI194904
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: 05/04/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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HIV Activation by Targeted BRD4 Recruitment - PROJECT SUMMARY Targeted HIV latency reversal remains a significant obstacle to HIV cure strategies. Most strategies rely on activation or inhibition of host proteins due to the lack of expressed viral proteins. However, studies suggest single LRAs cannot overcome the heterogeneity of the viral reservoir and the multiple mechanisms which aid to maintain latency, driving the field towards combination LRAs which risk increased off-target effects. Bifunctional molecules, which bridge two molecular complexes not expected to interact, represent a rapidly expanding field and a new potential avenue for development of novel latency reversal agents. Towards this aim, we have sought to identify potential warheads for targeted HIV latency reversal. Latent HIV infection produces no detectable viral proteins and fully elongated HIV mRNA is rare. However, small abortive transcripts containing the viral RNA TAR, which is recognized by the arginine-rich domain of the viral protein Tat, are observed in cells from durably suppressed individuals. Peptides which mimic the arginine-rich domain of Tat and bind TAR with low nanomolar affinities have been reported, representing viable ligands for TAR as one half of a bifunctional molecule. A critical role of Tat is the hijacking of P-TEFb, a host complex necessary for processive transcriptional elongation and full viral replication. Current LRAs can modulate P-TEFb levels, but in the absence of Tat during latency there are no current strategies which mediate direct recruitment of P-TEFb to the HIV promoter. As such, a targeted therapeutic that directly recruits P-TEFb to the HIV LTR is an attractive strategy. We have recently observed that in contrast to the long-standing dogma, the bromodomain inhibitor family of LRAs does not release competition between Tat and BRD4 for P-TEFb. Rather, bromodomain inhibitors increase free, active BRD4/P-TEFb. This in turn triggers an altered transcriptional response which positively impacts viral activation in the absence of Tat. This transcriptional response is independent of the bromodomains. This is key to the development of bifunctional molecules, as the molecule must recruit relevant complexes but not interfere with necessary activity. Targeted recruitment of BRD4 to epigenetically silenced host gene promoters has previously been shown to activate transcription. These approaches used bromodomain inhibitors as warheads and have shown selective BRD4 binding and increased phosphorylated RNAPolII. We hypothesize that targeted recruitment of the endogenous BRD4/P-TEFb complex to the HIV LTR using TAR-binding peptides linked to a bromodomain inhibitor will result in selective viral activation. Towards this aim, we have generated a proof-of-concept molecule, Tat14-JQ1, a 14 amino acid peptide containing the RNA-binding domain of Tat conjugated to the bromodomain inhibitor JQ1. We demonstrate this molecule can induce HIV in cell models. Here we seek to define the mechanism and selectivity for a first-in-class targeted latency reversal agent, Tat14-JQ1, designed to recruit an endogenous transcriptionally activating complex directly to the HIV LTR for 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: 2026 ( Subtotal = $194,375 )
2026	2026	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	1	5/5/2026	NEW	$194,375
														Subtotal = $194,375

Grand Total All Awards = $194,375

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HIV Activation by Targeted BRD4 Recruitment

Award Number: R21AI194904

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: 05/04/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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