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Regulation of HIV-1 transcription reactivation potential by transcription factor density and composition

Award Number: R01AI198076
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: 02/06/2026
PERIOD OF PERFORMANCE END DATE: 01/31/2031

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Regulation of HIV-1 transcription reactivation potential by transcription factor density and composition - PROJECT SUMMARY Although HIV-1 infection can be controlled through long-term treatment with anti-retroviral therapy (ART), a true cure has been elusive. Reservoir cells persist over time and support latent HIV-1 reactivation upon therapy cessation, yet little is known about the underlying molecular mechanisms. Our lab has recently identified previously unknown facets in the HIV-1 transcriptional program that we will explore in this proposal to help fill this knowledge gap, and may offer key insights into HIV-1 biology as well as cure strategies. The major goal of this grant application is to understand the role of transcription factors (TFs) in reservoir cells and Tat in first igniting and then sustaining the HIV-1 transcription reactivation program. We will accomplish this goal by leveraging genetic and genomic approaches to explore HIV-1 transcription at high-resolution in several immortalized cell models of latency and then cross-validate the data in samples from HIV-1 infected participants. Our recent studies have revealed that HIV-1 transcription reactivation proceeds through a previously unknown two-step mechanism: first ignited by transcription initiation through de novo Pol II recruitment (host phase) and later sustained by synchronization of pause release with re-initiation (viral phase). These two steps are the major transcriptional bottlenecks in the HIV-1 transcriptional program for a functional cure. Overcoming these bottlenecks guarantees a transcriptional switch that facilitates efficient latency reactivation. We will focus on defining the molecular mechanisms supporting HIV-1 transcription reactivation throughout the multi-phase HIV-1 transcription program. Specifically, we will explore the unifying central hypothesis that the composition and density of TFs at the proviral genome dictates the initial wave of HIV-1 transcription reactivation directly influencing Tat function and reactivation potential. We will examine the roles of the integration site, ligands stimulating reservoir cells and the interplay between TFs and chromatin accessibility. These goals are reflected in two Specific Aims: to define the relevance of TFs in reservoir cells that initiate and sustain HIV-1 reactivation (Aim 1), and to explore the interplay between TFs and chromatin accessibility during the transcriptional switch that facilitates efficient latency reactivation (Aim 2). If successful, this project will yield a better understanding of the molecular mechanisms by which TFs in reservoir cells and Tat converge to promote efficient HIV-1 transcription and latency reactivation, collectively having a sustained impact in the field. In keeping with NIAID’s mission of ending the HIV-1 epidemic, our long-term objective is to force the basic discoveries to devise alternative cure strategies. Thus, the fundamental knowledge to be gained could be used in future studies beyond the scope of this study, to exploit the transcriptional bottlenecks for functional cure approaches.


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 = $828,340 )
2026	2026	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Allergy and Infectious Diseases Research	000	1	2/6/2026	NEW	$828,340
														Subtotal = $828,340

Grand Total All Awards = $828,340

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Regulation of HIV-1 transcription reactivation potential by transcription factor density and composition

Award Number: R01AI198076

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: 02/06/2026

PERIOD OF PERFORMANCE END DATE: 01/31/2031

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