# Potent inhibition of HIV-1 latency reversal by PF 03758309

> **NIH NIH R21** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $225,772

## Abstract

SUMMARY
The persistence of latent, replication-competent HIV-1 proviruses in resting CD4+ T cells represents a major
barrier to curing HIV-1 infection. To date, efforts to eradicate this viral reservoir via the shock and kill approach
have not led to complete, long term viral suppression in either cell and/or animal models. Thus, we need to
consider alternate approaches that could lead to a sterilizing or functional cure for HIV-1 infection. The block
and lock approach seeks to silence the transcriptional activity of latent proviruses, such that when antiretroviral
therapy (ART) is removed viral rebound is significantly delayed or, better yet, prevented. Several research
groups have identified small molecule inhibitors that target different factors of the HIV-1 transcription
machinery, leading to a block and lock phenotype. However, blocking only one transcription pathway may not
be sufficient to silence all proviruses, and thus it is likely that successful implementation of this strategy will
require a combination of inhibitors. In this regard, there is a critical need to identify new molecules with different
mechanisms of action. Our laboratory recently discovered that the p21-activated kinase (PAK) inhibitor PF-
03758309 is an exceptionally potent inhibitor of HIV-1 latency reactivation (IC50 in the pM to low nM range) with
a huge selectivity index (> 3,000). (The discovery of PF-03758309 as an inhibitor of HIV-1 latency reversal is
described in: Vargas B, Giacobbi NS, Sanyal A, Venkatachari NJ, Han F, Gupta P, Sluis-Cremer N.
Antimicrob Agents Chemother. Inhibitors of Signaling Pathways That Block Reversal of HIV-1 Latency. 2019
Jan 29;63(2). pii: e01744-18.) In the long term, we anticipate that PF-03758309 alone, or in combination with
other drugs, could be used to facilitate a “block and lock” sterilizing cure in HIV-infected individuals. However,
we do not know the mechanism(s) by which this inhibitor abrogates the reactivation of latent HIV-1 infection in
CD4+ T cells. Indeed, preliminary studies in our laboratory revealed that its inhibition of HIV-1 latency reversal
is not due to inhibition of the PAKs. Accordingly, the primary goal of this R21 proposal is to elucidate the
mechanism(s) by which PF-03758309 silences HIV-1 proviruses.

## Key facts

- **NIH application ID:** 10326435
- **Project number:** 1R21AI157392-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** NICOLAS PAUL SLUIS-CREMER
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $225,772
- **Award type:** 1
- **Project period:** 2021-05-24 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10326435

## Citation

> US National Institutes of Health, RePORTER application 10326435, Potent inhibition of HIV-1 latency reversal by PF 03758309 (1R21AI157392-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10326435. Licensed CC0.

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