# NIH grant: ATPase Chromatin Remodeling Complexes as Modulators of HIV-1 Latency and Therapeutic Targets (1R01AI200543-01) — retained record

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source: [us-gov-api](https://highsignal.app/data/us-gov-api) (us-gov-api:nih-reporter)  published 2026-06-18 00:00 ingested 2026-06-28 12:46

[original source ↗](https://reporter.nih.gov/project-details/1R01AI200543-01)

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NIH grant 1R01AI200543-01: ATPase Chromatin Remodeling Complexes as Modulators of HIV-1 Latency and Therapeutic Targets
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Susana T Valente. Award: $3389992.
Start: 2026-06-18T00:00:00.
Abstract
Significance: HIV persists in long-lived CD4⁺ T cell reservoirs despite suppressive ART, as
integrated proviruses remain poised for reactivation. Chromatin remodeling is a central barrier to
durable silencing, yet most studies have focused on SWI/SNF family members. The roles of non-
SWI/SNF remodelers remain poorly defined, limiting our ability to rationally design host-directed
“block-and-lock” cure strategies. Our unbiased shRNA screen of all 16 human remodeler
ATPases identified EP400, CHD1, and CHD9 as repressors and INO80A, SMARCA5, and CHD2
as activators, establishing chromatin remodeling as a key determinant of HIV latency.
Innovation: Our prior studies revealed that the p400 complex regulates HIV transcription through
dual mechanisms: directly, by engaging Tat via the DMAP1 subunit to block Tat-TAR RNA
interactions and restrict p-TEFb recruitment; and indirectly, by altering host transcriptional
programs that control T cell activation states. Building on this mechanistic precedent and
methodological platform, we now focus on INO80A, SMARCA5, CHD1, and CHD2, remodelers
from distinct ATPase families that govern Tat-independent checkpoints at initiation, pause
release, and elongation. Methodologically, we will apply TurboID-ChAP-MS (locus-specific
proteomics), BEM-seq (single-nucleosome mapping), and degron-mediated acute depletion with
ATPase-dead rescue to interrogate remodeler function with unprecedented resolution.
Approach: Aim 1 will define the ATPase requirement and transcriptional checkpoints regulated
by INO80A, SMARCA5, CHD1, and CHD2 using degron/CRISPR perturbations, ChIP-seq,
nascent RNA profiling, and nucleosome mapping. Aim 2 will characterize remodeler-specific
complexes and Tat dependence at the HIV promoter via TurboID proximity labeling integrated
with chromatin affinity purification-mass spectrometry. Aim 3 will test combinatorial perturbations
in Jurkat and primary CD4⁺ T cell latency models, including ART-suppressed donor cells, to
identify synergistic “block-and-lock” strategies that enforce durable proviral silencing.
Impact: By defining remodeler-specific mechanisms at discrete transcriptional checkpoints and
leveraging their enzymatic, druggable activities, this work will establish chromatin remodeling as
a therapeutic axis for durable HIV suppression and functional cure.
```



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