# 5-Lipoxygenase Inhibition as a Therapy to Prevent Cryptococcus-related IRIS

> **NIH NIH R21** · TEXAS CHRISTIAN UNIVERSITY · 2021 · $170,219

## Abstract

Cryptococcal meningoencephalitis (CM) is the most common disseminated fungal disease in
AIDS patients and is responsible for 15% of AIDS-related deaths globally. A complication
associated with the initiation of antiretroviral therapy (ART) in HIV positive patients with CM is the
development of immune reconstitution inflammatory syndrome (IRIS) which can lead to severe
neurological sequela, morbidity, and significant mortality. IRIS afflicts up to 30% of HIV positive
patients with a prior diagnosis of cryptococcosis who begin ART. Current efforts to mitigate
Cryptococcus-related IRIS (C-IRIS) include delaying initiation of ART until sterile immunity is
achieved, and/or using corticosteroid and/or non-steroidal anti-inflammatory drugs (NSAIDs) as
anti-inflammatory agents to prevent C-IRIS. Significant drawbacks to these efforts are that
delaying ART therapy in HIV positive patients allows the virus to propagate unchecked and anti-
inflammatory drugs can inhibit host immune responses and potentially reduce anti-cryptococcal
drug activity. Thus, therapies that allow for ART initiation at the onset of diagnosis, do not inhibit
the efficacy of antifungal drugs or protective anti-cryptococcal host responses, and prevent
deleterious inflammatory responses will have a significant impact towards reducing morbidity
associated with C-IRIS. Preliminary studies in our laboratory show that inhibition of 5-
lipoxygenase (5-LO) activity results in a significant reduction in the neurological deterioration,
morbidity and mortality associated with CM. Specifically, studies using an experimental mouse
model of cryptococcosis show that 5-LO knockout (KO) mice, in contrast to wild-type (WT) mice,
do not exhibit the classic neurological sequela or mortality associated with CM. Moreover,
myeloid cell infiltration and the production of chemokines associated with the development of C-
IRIS in humans (i.e., CCL2 and CCL3) were significantly reduced in brain tissues of 5-LO KO
mice compared to WT mice. Taken together, these results lead us to hypothesize that inhibition
of 5-LO signaling reduces the neurological inflammatory sequelae leading to the
development of C-IRIS. To test our hypothesis, we propose to: 1) determine the impact of 5-
LO blockade on the development of C-IRIS and 2) demonstrate the therapeutic impact of 5-LO
inhibitors as an adjunct to antifungal therapy using a murine model of C-IRIS.

## Key facts

- **NIH application ID:** 10256128
- **Project number:** 1R21AI158260-01A1
- **Recipient organization:** TEXAS CHRISTIAN UNIVERSITY
- **Principal Investigator:** Floyd L. Wormley
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $170,219
- **Award type:** 1
- **Project period:** 2021-02-22 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10256128

## Citation

> US National Institutes of Health, RePORTER application 10256128, 5-Lipoxygenase Inhibition as a Therapy to Prevent Cryptococcus-related IRIS (1R21AI158260-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10256128. Licensed CC0.

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