# Epigenetic mechanisms underlying cannabinoid modulation of neuroinflammation in HIV/SIV infection

> **NIH NIH R01** · TEXAS BIOMEDICAL RESEARCH INSTITUTE · 2020 · $730,433

## Abstract

ABSTRACT
HIV associated neurological disorder (HAND), a major comorbidity affecting about 30-50% of patients receiving
suppressive anti-retroviral therapy is characterized by difficulties with attention, concentration, decision making
and memory, depression and slowed movements. Although chronic activation of brain microglia is proposed to
drive HAND, the molecular mechanisms remain ill defined. Emerging evidence has shown that epigenetic
mechanisms involving aberrant DNA methylation may significantly contribute to the pathogenesis of multiple
sclerosis, Parkinson’s and Alzheimer’s disease. Nevertheless, the role of DNA methylation specifically in HIV
induced monocyte/microglia activation remains unknown. The fact that epigenetic marks are heritable and
passed on to several generations of daughter cells during mitosis might explain a potential mechanism causing
monocyte/microglial activation that may in turn help maintain persistent neuroinflammation in cART treated
patients. Our preliminary studies identified significant upregulation of proinflammatory interferon stimulated and
chemokine genes in basal ganglia and marked alterations in DNA methylation of CpG islands in promoters of
genes associated with inflammatory response, apoptosis, dsDNA damage response and oxidative stress in
colonic epithelium of chronically SIV-infected macaques, respectively. More importantly, chronic cannabinoid
treatment to ART naïve SIV-infected rhesus macaques prevented proinflammatory gene expression in brain and
epigenetic alterations suggesting their immense therapeutic potential for attenuating neuroinflammation and
reduced HAND related symptoms. In the proposed studies, we will for the first time investigate changes in DNA
methylation associated with delta-9-tetrahydrocannabinol (THC), cannabidiol, JWH133 (CB2R agonist) induced
suppression of monocyte/microglial activation through the course of SIV infection. Further, we will determine the
effect of combination anti-retroviral treatment (cART) in conjunction with chronic cannabinoid treatments on
epigenetic alterations, viral reservoir, inflammation and endogenous cannabinoid levels in the blood and
cerebrospinal fluid. Finally, we will investigate the receptor mediated and molecular mechanisms by which THC
blocks endoplasmic reticulum stress, a key event in the onset of neurodegenerative diseases. The proposed
research is highly innovative and applies state of the art immunological and molecular approaches to fill a
significant gap in our understanding of the epigenetic mechanisms associated with HAND. As cannabinoids have
shown great promise for the treatment of neurological disorders, the proposed studies are necessary, as it will
provide a fundamental understanding of the epigenetic and endocannabinoid mechanisms underlying their anti-
inflammatory effects. Finally, the results will have important therapeutic implications for immune modulation in
not only HIV but also other chronic neuroinflammatory disease...

## Key facts

- **NIH application ID:** 10126610
- **Project number:** 1R01DA052845-01
- **Recipient organization:** TEXAS BIOMEDICAL RESEARCH INSTITUTE
- **Principal Investigator:** Siddappa N Byrareddy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $730,433
- **Award type:** 1
- **Project period:** 2020-09-30 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10126610

## Citation

> US National Institutes of Health, RePORTER application 10126610, Epigenetic mechanisms underlying cannabinoid modulation of neuroinflammation in HIV/SIV infection (1R01DA052845-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10126610. Licensed CC0.

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