# Novel role of inflammasome activation in ART neurotoxicity

> **NIH NIH R21** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2020 · $230,250

## Abstract

ABSTRACT
Toxicity of ART contributes to brain pathology and cognitive decline observed in HIV-infected
individuals; however, the mechanisms are not fully understood. The importance of ART toxicity
has been further enhanced by the introduction of pre-exposure prophylaxis (PrEP) into HIV
prevention. The blood-brain barrier (BBB) is on the first line of exposure to antiretroviral drugs,
making the brain endothelium particularly relevant in studies on toxicity of ART. While
antiretroviral drugs frequently achieve only sub-therapeutic levels in the brain parenchyma, their
plasma concertations are sufficient to negatively impact the brain vasculature, making the brain
endothelium the main target of ART toxicity in the CNS. The current application is based on our
exciting findings indicating that ART exposure results in mitochondrial dysfunction and alterations
of neurogenesis of neural progenitor cells (NPCs). Mitochondrial dysregulation is a strong inducer
of inflammasome, and indeed, our results implicate inflammasome activation in ART-induced
cerebral vascular toxicity. Mechanistically, the proposed work is focused on a novel pathway of
intercellular communication between the brain endothelium and perivascular NPCs via activation
of inflammasome. The central hypothesis is that ART activates inflammasome in brain
endothelial cells, followed by release of IL1β, which then affects adult neurogenesis of
NPCs, diminishing their differentiation into mature neurons and contributing to cognitive
decline. Throughout the proposal, we will differentiate the impact of ART with high CNS
penetrating efficacy (CPE) vs. ART with low CPE. Our application offers a unique, mechanistic,
and translational perspective on ART-induced toxicity and neuroinflammation that results in
cognitive impairment. The completion of the proposed study promises to establish new
therapeutic targets to protect against toxicity of ART.

## Key facts

- **NIH application ID:** 9925422
- **Project number:** 1R21MH122235-01
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Michal Toborek
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $230,250
- **Award type:** 1
- **Project period:** 2020-05-12 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9925422

## Citation

> US National Institutes of Health, RePORTER application 9925422, Novel role of inflammasome activation in ART neurotoxicity (1R21MH122235-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9925422. Licensed CC0.

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