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Discovery and Basic Research

(M1530-04-22) Anti-Viral and Anti-Inflammatory Effects of Novel PPARγ Agonist, INT131, in an EcoHIV Mouse Model: Relevance to the Treatment of HIV-Associated Neurocognitive Disorders

Monday, October 21, 2024
3:30 PM – 4:30 PM MT
Purpose: Approximately 50% of individuals with HIV suffer from HIV-associated neurocognitive disorders (HAND), characterized by behavioral, motor, and cognitive declines linked with brain inflammation, astrocytic activation, and neuronal apoptosis. Peroxisome proliferator-activated receptor gamma (PPARγ), a transcription factor involved in regulating glucose/lipid metabolism, has also demonstrated potential for eliciting anti-HIV and anti-inflammatory responses in neurodegenerative diseases such as HAND and HIV-encephalitis. Our hypothesis centered on the concept  that stimulating PPARγ via a novel selective agonist, INT131, could potentially attenuate HIV-induced brain inflammation in vivo, using an ecotropic HIV-1 (EcoHIV) mouse model that simulates HAND. This study aimed to investigate the ability of INT131 to mitigate both the infectivity and inflammation in EcoHIV infected mice.

Methods: We quantified markers of interest using qPCR analysis, including viral genes, inflammatory cytokines/chemokines, blood-brain barrier (BBB) tight junction proteins, and examined BBB permeability applying the NaF permeability assay, 5 weeks post IP injection of saline or EcoHIV (4x106 pg/ml) in: i) non infected  mice, ii) infected EcoHIV mice, and iii) infected EcoHIV mice treated with osmotic pump administration of INT131 (20 mg/kg/day). We further assessed INT131's efficacy in reversing neurocognitive deficits in EcoHIV infected male mice through behavioral assessments.

Results: Osmotic pump administration of INT131 in EcoHIV mice significantly reduced the expression of viral genes, inflammatory markers and restored the expression of BBB markers to control levels. We also observed a restoration of BBB permeability, measured via the NaF assay with INT131 treatment in the EcoHIV mouse model. We further assessed INT131's efficacy in reversing neurocognitive deficits in EcoHIV infected male mice through behavioral assessments. We have shown that administering INT131 at a dose of 20 mg/kg/day via osmotic pumps for 28 days effectively reversed neurocognitive deficits in locomotion, learning, and working memory, while also decreasing anxiety levels in EcoHIV-infected mice.

Conclusion: Our findings suggest PPARγ as a potential molecular target for treating/preventing HIV-associated brain inflammation, BBB dysfunction, and potentially HAND. Future studies will investigate the PPARγ-mediated modulation of signaling pathways such as NF-κB and MAPK known to be involved in regulating inflammatory cascades and oxidative stress. Additionally, behavioral studies will be conducted in female mice to explore sex as a potential variable.

Acknowledgements: I have no conflicts of interest to disclose.