# Identification of drugs that induce terminal transcriptional silencing of latent HIV-1 infection

> **NIH NIH R33** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $689,627

## Abstract

As it is becoming increasingly clear that currently pursued HIV-1 reactivating strategies may not result
in therapeutic HIV-1 eradication, alternative eradication strategies need to be explored. We here propose to
develop terminal transcriptional silencing (TTS) strategies specific for latent HIV-1 infection events. TTS
strategies would have their biological equivalent in retro/lentiviral silencing. However, TTS would not target de
novo infection events, but have to transcriptionally silence pre-existing, latent provirus in the absence of viral
proteins, mostly RNA or non-integrated DNA that usually trigger the antiviral cellular response. Evidence for
the existence of cellular innate immune mechanisms that specifically target lentiviral infection is provided by
the fact that lentiviral silencing is a major roadblock for lentiviral-based gene therapy. The existence of innate
cellular defense mechanisms that can control pre-existing virus-style genome expression is suggested by the
existence of defense mechanisms against a related, evolutionary ancient class of “genomic intruders” called
retrotransposons. These defense mechanisms individually evolved in response to each different
retrotransposon class. Unfortunately, because of this specificity, mechanisms that continuously actively control
retrotransposons to suppress their genomic spread, actually are inactive against HIV-1. Specificity of TTS
strategies against HIV-1 infection is essential as, beyond the general consideration of toxicity issues of any
drug intervention, TTS strategies cannot cause (i) any interference with innate control mechanisms that
suppress retrotransposon activity or cause (ii) any interference with mechanisms that control epigenetic
silencing of genes in human cells. For the R61 phase, we propose an iterative approach that combines high
content analysis methods (ATAC-seq, RNA-seq, kinome array analysis) with pharmacological perturbation
screens to identify drug targets that specifically control the cellular innate antiviral response to HIV-1 infection.
The proposed research will take advantage of (i) a preexisting, large selection of HIV-1 reporter cells, (ii) the
finding that certain clinical HIV-1 and in particular HIV-2 strains cause a much more potent innate TTS
response than the commonly used laboratory adapted HIV-1 clones, and (iii) the finding that macrophages are
much more efficient in executing TTS than T cells. The deliverable of the R61 phase will be (1) the
identification of druggable targets that if pharmacologically addressed, enable TTS in latently HIV-1 infected T
cells and (2) HTS-compatible drug screening assays for the identification of TTS-inducing drugs against these
targets. In the R33 phase, we will perform the actual drug screens to identify TTS-inducing compounds.
Identified candidate compounds would be tested in primary cell models of latent infection and cell material
derived from HIV-1 patients. By the end of the R33 phase we expect to have i...

## Key facts

- **NIH application ID:** 10223169
- **Project number:** 5R33AI133679-05
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** OLAF KUTSCH
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $689,627
- **Award type:** 5
- **Project period:** 2017-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10223169

## Citation

> US National Institutes of Health, RePORTER application 10223169, Identification of drugs that induce terminal transcriptional silencing of latent HIV-1 infection (5R33AI133679-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10223169. Licensed CC0.

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