# NIH grant: TAR RNA binding to INI1/SMARCB1 and its role in HIV-1 transcription and latency reactivation (1R01AI198154-01A1) — retained record

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[original source ↗](https://reporter.nih.gov/project-details/1R01AI198154-01A1)

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NIH grant 1R01AI198154-01A1: TAR RNA binding to INI1/SMARCB1 and its role in HIV-1 transcription and latency reactivation
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Xiao  Heng. Award: $3204071.
Start: 2026-06-18T00:00:00.
Abstract
The goal of this application is to study the role of interplay between the components of chromatin remodeling
SWI/SNF (BAF complex) and HIV-1 transcription machinery, focusing on the interaction of a BAF component,
INI1 (Integrase Interactor 1) with TAR RNA. HIV-1 reservoirs are a mixture of latent cells harboring proviruses
silenced at transcriptional level. Cure strategies need a deeper understanding of HIV-1 transcriptional
regulation. HIV-1 transcription, initiated by RNA Pol II, pauses producing short TAR transcripts. pTEFb
recruitment to TAR by Tat overcomes this transcriptional pause, facilitating elongation. Beyond Tat, the
action of chromatin remodeling complexes (CRCs) is required to facilitate elongation. The BAF complexes
CBAF and PBAF play distinct roles. While CBAF represses proviral transcription by maintaining nucleosomes
in an unfavorable state, PBAF remodels nucleosomes to facilitate elongation. INI1 is a component of both
CBAF and PBAF, and its role in transcription is not fully understood. INI1 was identified as a binding partner for
HIV-1 integrase (IN) and exerts multifacted roles in virus assembly, production and morphogenesis. INI1 has
multiple functional domains. IN binding Rpt1 domain structurally mimics TAR RNA & is necessary for late
events. We have made a novel observation that another domain of INI1, the N-terminal Winged Helix DNA
binding domain (WHD) specifically binds to TAR RNA and that this interaction is necessary for mediating
HIV-1 transcriptional elongation. These exciting results suggest that different functional domains of INI1(Rpt1
and WHD) involved in “TAR RNA mimicry” or “TAR RNA binding” regulate distinct stages of replication. We
hypothesize that INI1 WHD domain-TAR interaction is necessary for recruitment of PBAF to HIV-1 LTR
for transcriptional elongation and latency reactivation. Disrupting this interaction results in
transcriptional repression. We will investigate the role of this novel INI1:TAR RNA interaction in HIV-1
transcription and latency reactivation. This is a multi-PI application involving Drs. Kalpana (HIV-1 virologist),
Heng (NMR biophysicist) and Zou (computational biologist/protein-RNA structure). In Aim 1, we will
characterize INI1-WHD:TAR interaction in vitro and in vivo via molecular/genetic analyses (Kalpana/Heng).
We will employ alanine scanning mutagenesis based on WHD NMR structure to test WHD:TAR interaction.
We will use biophysical & biochemical approaches to probe TAR structural elements required for this
interaction. In Aim 2, we will employ computational modeling and NMR to determine the structure of INI1-
WHD:TAR RNA complex (Zou/Heng). In Aim 3, we will determine the role of INI1:TAR interactions in HIV-1
transcription, latency reactivation and mechanism of action (Kalpana). We will analyze the effect of TAR-
Interaction-Defective (TID) INI1 mutants on transcription of LTR-reporters and full-length HIV in INI1-/- cells.
Latent cells in which TID-INI1 mutants are knocked in (KI) will be used to assess effect on reactivation via
RNA-FISH and qRT-PCR assays. Our studies will establish INI1:TAR interaction as a drug target.
Inhibiting this interaction could block latency reactivation promoting deep latency and advancing cure
strategies.
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