# Eradication of CNS HIV reservoirs through a first-in-class anti-tumor agent ONC201

> **NIH NIH R21** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $229,500

## Abstract

Project Summary/Abstract
 Despite combination antiretroviral therapy (ART), HIV-1 continues to form reservoirs in lymphoid, gut
and central nervous system (CNS). The HIV-1 brain reservoir is a pool of long-lived cells, which include
perivascular macrophages and microglia that can harbor replication-competent virus. Therapeutic interventions
that can effectively eliminate HIV in these CNS cells are urgently needed. FOXO3a, a powerful transcription
factor critical for aging and immune homeostasis, offers hope to eliminate HIV-1 reservoirs. Our previous
publications have demonstrated that FOXO3a and cytokine TNF-related apoptosis-inducing ligand (TRAIL)
target HIV-1-infected macrophages for apoptosis. Interestingly, there is an apparent lack of FOXO3a and
TRAIL signaling in the CNS during HIV-1 invasion. The deficiency of FOXO3a signaling and TRAIL expression
may inadvertently facilitate the forming of HIV-1 brain reservoirs. Therefore, FOXO3a may serve as a drug
target to clear HIV-1-infected macrophage and microglia during HIV-1 infection of the CNS. Our long-term
objective is to target FOXO3a/TRAIL pathway and make drug discoveries to improve treatment for people
living with HIV-1. We will take advantage of a recent drug development that provided ONC201 as a potent and
stable small molecule activator of FOXO3a/TRAIL pathway. ONC201 is orally active, has a wide safety margin,
and can cross the blood-brain barrier with favorable pharmacokinetics. Moreover, ONC201 has shown
efficacious antitumor effect in numerous solid tumors and hematological malignancies in preclinical models and
in clinical trials. We have obtained ONC201 and shown for the first time that ONC201 has anti-viral effects in
vitro and in a murine HIV-1 encephalitis model (Zhao et al, Antiviral Research, 2019). Furthermore, we have
performed preliminary studies demonstrating that ONC201 potentiates the anti-viral effect of ART drug and
delays viral rebound in vitro in macrophage cultures. We hypothesize that modulation of FOXO3a through the
first-in-class anti-tumor drug ONC201 will induce TRAIL and facilitate ART leading to HIV-1 elimination in CNS
reservoirs. In Aim 1, we will determine the utility of ART and ONC201 in HIV CNS eradication in the humanized
CD34-engrafted IL-34-transgenic mice as a model for neuroHIV. In Aim 2, we will elucidate the pathways
(mechanisms) responsible for ONC201-mediated viral clearance in macrophages, microglia, and T cells in
relation to FOXO3a/TRAIL during ART. To achieve these aims, we will use a “state of the art” humanized
mouse model and in vitro macrophage and T cell cultures and evaluate whether ONC201 and the standard
ART can synergistically reduce the CNS viral load and delay viral rebound. The proposed studies will provide
important proof-of-concept that endogenous FOXO3a could be harnessed by ONC201 to combat persistent
and latent HIV-1 infection. Understanding the interactions between immune control of HIV-1 infection and ART
will reveal ...

## Key facts

- **NIH application ID:** 10082772
- **Project number:** 1R21MH123384-01A1
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Yunlong Huang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $229,500
- **Award type:** 1
- **Project period:** 2020-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10082772

## Citation

> US National Institutes of Health, RePORTER application 10082772, Eradication of CNS HIV reservoirs through a first-in-class anti-tumor agent ONC201 (1R21MH123384-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10082772. Licensed CC0.

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