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Differential Effects of Cannabinoid Receptor 2 Agonists on HIV Replication and Inflammatory Activation in
Alexander Starr1, Sara Rathore1, Marzieh Daniali2
1Department of Oral Medicine, School of Dental Medicine, University of Pennsylvania, 240 S. 40th St, Rm 312 Levy, Philadelphia, PA, 19104, USA.
Abstract:
Emerging evidence suggests brain-resident myeloid cells, including perivascular macrophages and microglia, provide a reservoir for HIV infection in the central nervous system (CNS), and their inflammatory activation is a proposed pathogenic mechanism in HIV-associated neurocognitive disorders (HAND). We investigated whether cannabinoid receptor 2 (CB2), an immunomodulatory receptor expressed in myeloid cells, regulates viral replication and inflammation in HIV-infected macrophages and microglia. Using the synthetic CB2-specific agonist JWH-133, we found that CB2 activation reduced HIV replication in primary human monocyte-derived macrophages (MDMs) and human induced pluripotent stem cell-derived microglia (iMg) at differing doses, corresponding to the basal expression of CNR2, which encodes CB2, and related endocannabinoid transcripts in each cell type. JWH-133 broadly reduced release of cytokines from HIV-infected MDMs but not iMg. RNA-seq revealed that CB2 agonism primarily altered interferon and integrated stress response pathways in MDMs while altering homeostatic pathways, including synapse maintenance and phagocytosis, in iMg. Further analyses in iMg revealed that NLRP3 inflammasome activation, but not priming, was reduced by CB2 activation, which did not inhibit HIV-induced nuclear factor kB activation. This study identifies key differences in CB2 response between myeloid lineage cell types and implicates CB2-specific agonists as promising candidates for the regulation of HIV-associated neuroinflammation.
Insights
Cannabinoid receptor 2 (CB2) activation reduced HIV replication in macrophages and microglia. CB2 agonists may help regulate HIV-associated neuroinflammation by targeting distinct pathways in these brain cells.
Area of Science:
- Neuroimmunology
- Virology
- Pharmacology
Background:
- Brain-resident myeloid cells, like macrophages and microglia, are reservoirs for HIV.
- Inflammatory activation of these cells contributes to HIV-associated neurocognitive disorders (HAND).
- Cannabinoid receptor 2 (CB2) is an immunomodulatory receptor found on myeloid cells.
Purpose of the Study:
- To investigate if CB2 receptor activation regulates HIV replication and inflammation in macrophages and microglia.
- To explore the differential effects of CB2 agonism on these cell types.
Main Methods:
- Used a synthetic CB2-specific agonist (JWH-133) on primary human monocyte-derived macrophages (MDMs) and human induced pluripotent stem cell-derived microglia (iMg).
- Assessed HIV replication, cytokine release, and gene expression changes (RNA-seq).
- Investigated NLRP3 inflammasome and nuclear factor kB (NF-kB) activation.
Main Results:
- CB2 activation reduced HIV replication in both MDMs and iMg, with dose-dependency linked to CNR2 expression.
- JWH-133 decreased cytokine release in MDMs but not iMg.
- CB2 agonism modulated interferon and stress response pathways in MDMs, and homeostatic pathways in iMg.
- CB2 activation reduced NLRP3 inflammasome activation (but not priming) in iMg, without affecting HIV-induced NF-kB activation.
Conclusions:
- CB2 receptor response differs significantly between myeloid cell types (macrophages vs. microglia).
- CB2-specific agonists show potential for regulating HIV-associated neuroinflammation.
- Targeting CB2 offers a promising therapeutic strategy for HAND.
