# Inter- and Intra-cellular effects of cannabinoids, HIV and ART in the CNS

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $685,730

## Abstract

Abstract:
Antiretroviral therapy (ART) has dramatically extended the lives of people living with HIV (PLWH); however,
they continue to experience a plethora of co-morbid conditions including neuronal disorders and pain.
Between 40 and 72% of PLWH use cannabis to mitigate anxiety, stress, ART side effects, pain, and/or for
pleasure with over 55% of patients using cannabis at least daily. Interestingly, a recent study found that people
who use cannabis heavily had reduced inflammatory signatures in PLWH on ART. These and a numerous
other studies support the anti-inflammatory and immunomodulator effects of phytocannabinoids in a number of
organ systems including heart, colon, kidney, liver and the gut; however, their medicinal use is confounded by
the psychotropic activities. Efforts to separate the anti-inflammatory effects from the psychotropic effects have
revealed differential activities of 3 endogenous receptors including cannabis receptor 1 (CB2) CB2 which
exhibit differential tissue expression and agonism with endo- and phyto-cannabinoids. Several reports have
shown that cannabinoids attenuate HIV infection and/or replication in T-cells, macrophages, dendritic cells and
human fetal microglia cultured ex vivo. However, the effect of cannabinoids on HIV infection of microglia in the
context of ART and the normal cellular environment of neighboring neurons and astrocytes in the CNS has not
been examined. Several studies specifically implicate CB2 agonism which has been shown to have anti-
inflammatory properties in the heart, gut, experimental autoimmune encephalitis and neuropathic pain via
inflammasome activation. This has led us to hypothesize that Cannabinoid signaling influences HIV infection
and chronic inflammation in the presence of ARV in the central nervous system by attenuating the
inflammasome.
 In order to examine HIV infection in the context of cells of the CNS, we have developed a human
induced pluripotent stem cell tri-culture model composed of iNeurons, iAstrocytes, and iMicroglia. This model
recapitulates several key aspects of HIV infection in the CNS including increased cytokine production,
oxidative stress response, inflammatory signaling, and integrated stress response. ARV treatment reduces
HIV infection and inflammatory signaling pathways; however, a subset of pathways remain elevated despite
viral suppression. We propose to further develop this model to determine the ability of cannabinoids to
modulate HIV-induced inflammation and subsequent neuronal dysfunction via reducing inflammasome
activation by: 1) Determining the effect of cannabinoids on chronic HIV infection and ART in the context of
iMgl/iNrn/iAstr triculture. 2) Determining the effect of cannabinoids on cytokine levels, inflammatory gene
expression profile, and microglial activation in iMgl/iNrn/iAstr triculture. 3) Determining the effect of
cannabinoids on neurons and astrocytes in HIV infection and ART in iMgl/iNrn/iAstr triculture.

## Key facts

- **NIH application ID:** 10837044
- **Project number:** 5R01DA052826-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Kelly L Jordan-Sciutto
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $685,730
- **Award type:** 5
- **Project period:** 2020-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10837044

## Citation

> US National Institutes of Health, RePORTER application 10837044, Inter- and Intra-cellular effects of cannabinoids, HIV and ART in the CNS (5R01DA052826-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10837044. Licensed CC0.

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