# Exploration of novel block-and-lock agents alone and in combination for HIV remission in humanized mice

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2024 · $889,277

## Abstract

Abstract
 HIV-1 transcriptional inhibitors have immense potential in functional cure approaches and could transform the
way we treat HIV infections. Unlike current antiretroviral therapy (ART), transcriptional inhibitors offer the
prospect of reducing residual viremia derived from reservoir of long-lived cells containing integrated proviruses,
likely reducing ongoing the chronic immune activation, inflammation and HIV-associated co-morbidities still
experienced by ART-adherent individuals living with HIV. Furthermore, we believe transcriptional inhibitors are
amenable to block-and-lock functional cure approaches, aimed at the durable suppression of HIV in the absence
of daily therapy, through permanent epigenetic silencing of integrated proviruses. This hypothesis was founded
on the activity of the potent Tat inhibitor didehydro-Cortistatin A (dCA). In in vitro and in vivo models of HIV
latency, dCA inhibition of HIV transcription over time prompts the viral promoter into deep transcriptional
inhibition, limiting viral reactivation upon treatment interruption or with latency reactivating agents (LRAs).
Despite their great potential, there are still no HIV transcriptional inhibitors in the clinic, and challenges with the
cost of large-scale production of dCA are slowing its progression towards clinical studies.
 Here we propose to investigate the repurposing the FDA approved aldosterone antagonist Spironolactone (SP)
for HIV transcriptional inhibition. An off-target activity of SP is the degradation of the XPB subunit of the general
transcription factor TFIIH, a key player in RNAPII initiation at the transcriptional start site (TSS) of genes. We
demonstrated in vitro that SP treatment or shRNA knockdown of XPB selectively inhibits HIV transcription and
blocks viral reactivation from latency without global transcriptomic defects. This study highlighted the host factor
XPB as a novel drug target and SP as a potential block-and-lock agent. Here we propose to explore the potential
of SP, alone or in combination with dCA, as a block-and-lock agent in the humanized bone-marrow, thymus liver
(BLT) mouse model of HIV infection by: 1) Determine the relationship between SP treatment length with residual
viremia levels in tissues and correlates of chronic immune activation/inflammation in HIV infected ART-
suppressed BLT mice.; 2) Assess the ability of SP to maintain deep latency as a single drug in the absence of
ART and study viral resistance evolution; 3) Impact of dCA and SP in combination as front-line therapy on the
size of the established viral reservoir and time to viral rebound. We predict that longer treatment lengths of HIV
infected BLT mice with SP will correlate with improved reduction of low-grade HIV persistent transcription from
the viral reservoir and likely chronic immune activation. Importantly, we seek to demonstrate that once deep
transcriptional suppression is established, SP alone blocks viral rebound. In addition, when used as front-l...

## Key facts

- **NIH application ID:** 10812482
- **Project number:** 5R01AI177327-02
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** J. Victor Garcia-Martinez
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $889,277
- **Award type:** 5
- **Project period:** 2023-03-20 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10812482

## Citation

> US National Institutes of Health, RePORTER application 10812482, Exploration of novel block-and-lock agents alone and in combination for HIV remission in humanized mice (5R01AI177327-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10812482. Licensed CC0.

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