# Delving into a Unique Transcription Factor Family to Regulate HIV Transcription

> **NIH NIH R21** · UNIVERSITY OF FLORIDA · 2024 · $289,800

## Abstract

ABSTRACT
 The persistence of latently infected memory CD4+ T cells releasing a low-level trickling of viral RNAs and
proteins in people living with HIV (PLWH) on antiretroviral therapy (ART) provides a strong rationale for the
development of cure strategies. HIV functional cure approaches are being explored, at the transcriptional level,
to achieve sustained ART-free viral remission that would result from epigenetic changes over time. These
approaches are supported by evidence in PLWH who spontaneously control their viral load below the limit of
detection, in the absence of ART (elite controllers, ECs). These ECs were shown to have a large proportion of
their proviruses in condensed chromatin (heterochromatin) loci, with virus refractory to reactivation.
 The chromatin environment surrounding the HIV promoter is believed to be regulated by host transcription
factors, host chromatin remodelers and the viral Tat protein. Our hypothesis is that the pioneer factor (PF) family
may also remodel the HIV locus chromatin, via their unique epigenetic modulator properties, resulting in the
regulation of HIV transcription. PFs play critical roles in chromatin remodeling, mostly during development and
disease phenotypes. Unique properties of PFs include 1) trigger assembly of regulatory factors on target DNA
in heterochromatin; 2) bookmark genes for rapid reactivation/repression and 3) induce persistent epigenetic
modulation of the cellular chromatin. A few PFs were reported to modulate HIV latency and persistence in primary
CD4+ T cells but were poorly studied mechanistically. Preliminary data using shRNAs targeting 13 PFs in the
HIV latently infected CD4+ T cells, revealed 3 novel hits that hindered HIV transcription. This data further
highlights the significance of uncovering the role played by the PFs on HIV transcription in CD4+ T cells, with the
long-term goal to harness them for HIV cure approaches and/or diagnostic purposes. Here, we propose to:
Aim 1. Screen a shRNAmir library targeting 31 PFs (and controls) by flow cytometry, taking advantage of
the HIV reporter pMorpheus-V5 vector in Jurkat T cells. This vector allows the distinction of productively infected,
latently infected, and uninfected cells. The shRNAmir relative abundance in these populations will reflect their
activity on HIV transcription. The follow-up of the candidates will be based namely on reproducibility and novelty.
 Aim 2. Validate the hits identified in preliminary data and Aim 1. Their activity will be confirmed in cell line
models of latency with different HIV transcriptional environments, and in primary blood CD4+ T cells from
uninfected and virally suppressed ART treated female and male donors since estrogen modulates certain PFs’
activity. Their impact on CD4+ T cell proliferation, activation and cytotoxicity will also be measured.
 Aim 3. Characterize the 3 hits identified in preliminary data. Their recruitment to the host/HIV promoters
(ChIP-Seq analysis), their modulatio...

## Key facts

- **NIH application ID:** 11007923
- **Project number:** 1R21AI186602-01
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Sonia Mediouni Jablonski
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $289,800
- **Award type:** 1
- **Project period:** 2024-07-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11007923

## Citation

> US National Institutes of Health, RePORTER application 11007923, Delving into a Unique Transcription Factor Family to Regulate HIV Transcription (1R21AI186602-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/11007923. Licensed CC0.

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