Targeting super-enhancers to regulate HIV transcription and latency

The National Institute of Allergy and Infectious Diseases awarded $297,000 to Texas Biomedical Research Institute on September 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to fund research on targeting super-enhancers to regulate HIV transcription and latency.

The project, identified as R21AI203697, will define molecular mechanisms by which super-enhancer-associated long non-coding RNAs (SE-lncRNAs) regulate HIV transcription and maintain viral latency in resting CD4 T cells, and will functionally characterize a network of SE-lncRNAs governing HIV transcription and latency. The research addresses the barrier posed by latent HIV reservoirs that persist despite antiretroviral therapy and drive rapid viral rebound upon treatment interruption, and seeks to develop precise, host-directed strategies for selective reactivation of latent virus as an alternative to current latency-reversing agents that lack specificity and potency.

Texas Biomedical Research Institute, doing business as Southwest Foundation for Biomedical Research, serves as the recipient. The institute operates the Southwest National Primate Research Center in San Antonio, Texas, where performance will take place. The period of performance runs from September 1, 2026, through August 31, 2028. This is a Project Grant, an assistance type used by NIH to fund discrete, circumscribed research projects proposed by an investigator.

Abstract

Although antiretroviral therapy (art) effectively suppresses viremia, human immunodeficiency virus (HIV) persists in long-lived latent reservoirs, primarily within resting CD4⁺ T cells. These transcriptionally silent but replication-competent proviruses evade immune clearance and drive rapid viral rebound upon treatment interruption, necessitating lifelong art. Intermittent viral transcription from these reservoirs also contributes to chronic immune activation and HIV-associated comorbidities. A major barrier to achieving a functional cure is the incomplete understanding of host regulatory mechanisms that maintain or release HIV latency. Current latency-reversing agents (LRAS) lack specificity and potency and often induce global immune activation, underscoring the need for precise, host-directed strategies to selectively reactivate latent HIV. Long non-coding rnas (LNCRNAS), particularly super-enhancer-associated LNCRNAS (SE-LNCRNAS), are emerging as critical regulators of transcriptional programs. Our preliminary data show that HIV infection modulates a subset of SE-LNCRNAS in CD4⁺ T cells and that targeted silencing of specific SE-LNCRNAS enhances HIV transcription. We identified a novel SE-lncrna (sea; ENSG00000273230) that regulates integrator complex subunit 1 (INTS1) expression. INTS1 is a component of the integrator complex that represses including HIV transcription. These findings suggest that SE-LNCRNAS form host regulatory circuits that actively maintain HIV latency. We hypothesize that SE-LNCRNAS control HIV transcription and latency by scaffolding transcriptional regulators at viral and cellular loci, and that selective disruption of these rnas can reverse latency. To test this hypothesis, we will (1) define the molecular mechanisms by which sea regulates INTS1 gene transcription and (2) functionally characterize a network of SE-LNCRNAS that governs HIV transcription and latency. Aim 2 will use pooled single-cell RNA perturbation to identify and prioritize additional SE-LNCRNAS with reproducible effects on HIV transcription. Together, these studies will define a new class of host regulators of HIV transcription and latency and provide a foundation for future mechanistic and translational studies.