# Cannabinoid Modulation of Neuroinflammation in Human iPSC Models of HIV Infection

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2021 · $46,036

## Abstract

PROJECT SUMMARY / ABSTRACT
 Despite effective combined antiretroviral therapies, 30-50% of people living with human
immunodeficiency virus-1 (HIV) infection experience mood, memory, learning, and/or motor disfunction,
collectively labeled HIV associated neurocognitive disorders. Mounting evidence suggests that HIV infects
brain-resident macrophages and microglia, providing a persistent reservoir for HIV replication in the central
nervous system. Because HIV does not infect neurons, the neurotoxic mechanisms driving neurocognitive
decline are likely mediated by infected glia, which become activated and secrete proinflammatory cytokines
and chemokines, neurotoxic HIV components, and excitotoxic levels of glutamate. Activation of the NLRP3
inflammasome, an NF-κB-driven assembly that facilitates IL-1β and IL-18 release and initiates pyroptosis, has
been identified as an HIV-induced mediator of neurotoxicity. Recent studies suggest that NLRP3 activation is
suppressed by activation of cannabinoid receptor 2 (CB2), an immunomodulatory GPCR which has been
separately identified as a neuroprotective target in in vitro HIV models. I hypothesize that CB2 agonism
decreases HIV-associated macrophage/microglial activation and macrophage/microglia-mediated neurotoxicity
by suppressing the NLRP3 inflammasome. This proposal leverages primary human monocyte-derived
macrophages (MDMs) in parallel with human induced pluripotent stem cells (iPSC) differentiated into microglia
(iMg) and glutamatergic cortical neurons to understand the cell-specific effects of CB2 agonists on HIV infection
and subsequent neuroinflammation. This will be accomplished in three aims: (I) identify how CB2 agonism
effects macrophage and microglial infection dynamics, broad pro-inflammatory activation, and
endocannabinoid system component expression in human models exposed to intact HIV, (II) specifically
determine the effects of CB2 agonism on NLRP3 inflammasome priming, assembly, and pro-inflammatory
cytokine release, and (III) examine whether CB2 agonism is protective against indirect macrophage- and
microglia-mediated neurotoxicity, and whether that protection occurs via modulation of the NLRP3
inflammasome. These studies will increase our understanding of the effects of cannabinoid exposure in HIV-
induced neuroinflammation and determine whether CB2 is a potential therapeutic target for NLRP3
inflammasome suppression in HIV infection and other pathologic neuroinflammatory contexts.

## Key facts

- **NIH application ID:** 10257502
- **Project number:** 1F31DA054001-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** ALEXANDER STARR
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 1
- **Project period:** 2021-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10257502

## Citation

> US National Institutes of Health, RePORTER application 10257502, Cannabinoid Modulation of Neuroinflammation in Human iPSC Models of HIV Infection (1F31DA054001-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10257502. Licensed CC0.

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