# Targeting Immunometabolism: a novel role for itaconate in the treatment of HIV-associated neurocognitive disorder and cocaine use disorder

> **NIH NIH R21** · UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA · 2024 · $181,708

## Abstract

HIV Associated Neurocognitive Disorder (HAND) is one of the most common and clinically important
complications of HIV infection. There is an urgent need for effective therapeutic strategies for HAND exacerbated
by Cocaine Use Disorder (CUD). Through an extensive analysis of the HIV-induced transcriptome, we
determined that HIV and cocaine profoundly induce overexpression of the microglia-specific gene aconitate
decarboxylase 1 (acod1). Acod1 converts the tricarboxylic acid (TCA) intermediate cis-aconitate to itaconate
during inflammation. Itaconate activates anti-inflammatory transcription factors thereby protecting macrophages
from infection-triggered cell death. Although the attenuation of inflammation by itaconate has been characterized
in peripheral macrophages, the role of immunometabolism, including itaconate production, has not been studied
in HIV and cocaine-exposed microglia. This innovative proposal will characterize novel targets of itaconate action
in the brain. The hypothesis of this proposal is that itaconate balances neuroinflammation by activating
anti-inflammatory pathways in HIV-infected microglia cells, consequently cell death is attenuated
allowing microglial HIV reservoirs to be maintained. Further, we hypothesize that inhibition of itaconate
synthesis and downstream pathways in HIV-infected microglia has the potential to selectively eliminate HIV
reservoirs in the brain tissues – i.e., an innovative “Non-activating Shock and Kill” cure approach. In contrast, we
will also explore the strong anti-inflammatory potential of the cell- and blood-brain barrier (BBB)-penetrating
modified derivatives of itaconate -- dimethyl Itaconate (DMI) and 4-octyl-itaconate. Our preliminary results show
that 4-octyl-itaconate protects primary neurons from HIV-tat and cocaine toxicity. Thus sustained activation of
itaconate pathways by BBB-penetrable itaconate derivatives may be an alternative approach for the
treatment of HAND worsened by CUD. This innovative proposal employs a novel approach centered on
immunomeabolism that has not been considered in targeting HIV-infected microglia. Esters of other metabolites,
including fumarate, are already approved for inflammatory diseases such as psoriasis and arthritis, increasing
the clinical relevance of these exciting studies.

## Key facts

- **NIH application ID:** 10819587
- **Project number:** 5R21DA058586-02
- **Recipient organization:** UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
- **Principal Investigator:** Rosemarie M Booze
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $181,708
- **Award type:** 5
- **Project period:** 2023-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10819587

## Citation

> US National Institutes of Health, RePORTER application 10819587, Targeting Immunometabolism: a novel role for itaconate in the treatment of HIV-associated neurocognitive disorder and cocaine use disorder (5R21DA058586-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10819587. Licensed CC0.

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