# Impact of Dead Box RNA Helicase 3 signaling on HIV-1 Tat- and cocaine-induced neurotoxicity

> **NIH NIH R21** · UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA · 2020 · $185,493

## Abstract

HIV Associated Neurocognitive Disorder (HAND) is one of the most common and clinically important
complications of HIV infection. Neurotoxicity is due to the accumulation of HIV-encoded Trans Activator of
Transcription (Tat) and other viral proteins released from infected cells. Neuronal damage in HIV-infected
patients is significantly exacerbated by drug abuse. Thus, there is an urgent and increasing need for effective
therapeutic strategies for HAND. We utilized a computational approach in our NIH-funded work to uncover DEAD
Box RNA Helicase 3 (DDX3) as a potential target in HAND. DDX3 was recently established as a target protein
for cancer therapy. A selective small molecule inhibitor of DDX3 helicase activity, RK-33, has recently been
developed and tested in animal models of lung cancer. However, DDX3 has never been proposed to be involved
in HAND development, and RK-33 has never been tested in models of HAND or other neurodegenerative
diseases. We therefore analyzed the effects of the DDX3 inhibitor RK-33 on the viability of Tat/cocaine-treated
primary mouse cortical neurons. Our preliminary results show that RK-33 protects these neurons against the
damage caused by a combined insult of Tat and cocaine, and that the effect was quite robust. Thus, the
hypothesis of this proposal is that the activity of DDX3 promotes drug-induced HAND-associated
neuropathology via pathological Stress Granules (SGs), and the inhibition of DDX3 enzymatic activity
alleviates this neurotoxicity by interfering with pathological SG formation. The main goal of the proposal
is to establish DDX3 as a target for anti-HAND drug development, validate that pharmacological inhibition of
DDX33, can be a treatment for HAND, and also uncover important mechanistic links in HAND neuropathology.
Aim 1 will determine the mechanism of RK-33 protection of cortical neurons from the combined neurotoxicity of
Tat and cocaine. Published evidence suggests that Tat interacts with DDX3, and that this interaction depends
on the enzymatic activity of DDX3. We propose that Tat interacts with DDX3 to facilitate Tat/cocaine compounded
neurotoxicity, and the protective effects of RK-33 result from inhibition of DDX3’s enzymatic activity. Aim 2 will
establish the function of SGs as a central regulator of the protective effects of RK-33 inhibition against Tat
/cocaine-induced neurotoxicity. DDX3 is a core component of SGs and is believed to directly participate in their
assembly. The accumulation of pathological SGs is a noticeable feature of amyotrophic lateral sclerosis and
other neurodegenerative diseases. We propose that DDX3 inhibition by RK-33 protects the neurons from
Tat/cocaine by impairing pathological SG assembly and dynamics. Over the course of this project, the role of
DDX3 in the pathology of HAND will be better understood. Determining a connection of DDX3 to pathology
associated with SGs could have much broader implications for many other neurodegenerative diseases. Going
forward, ph...

## Key facts

- **NIH application ID:** 9858322
- **Project number:** 5R21DA047936-02
- **Recipient organization:** UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
- **Principal Investigator:** Michael Shtutman
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $185,493
- **Award type:** 5
- **Project period:** 2019-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9858322

## Citation

> US National Institutes of Health, RePORTER application 9858322, Impact of Dead Box RNA Helicase 3 signaling on HIV-1 Tat- and cocaine-induced neurotoxicity (5R21DA047936-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9858322. Licensed CC0.

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