CB2 Receptor Activation Reduced HIV Replication in Brain Immune Cells

CB2 activation with JWH-133 reduced HIV replication in primary macrophages and iPSC-derived microglia at different doses corresponding to each cell type's basal endocannabinoid expression. JWH-133 broadly reduced cytokine release from HIV-infected macrophages but not microglia. In microglia, CB2 activation reduced NLRP3 inflammasome activation without affecting NF-kB signaling. RNA-seq revealed distinct pathway effects: interferon/stress response in macrophages vs. homeostatic pathways in microglia.

In vitro study using primary human monocyte-derived macrophages and iPSC-derived microglia infected with HIV and treated with the CB2-specific agonist JWH-133. Assessed HIV replication, cytokine release, RNA-seq transcriptomics, and inflammasome activation.

Brain-resident immune cells serve as HIV reservoirs in the central nervous system and drive neuroinflammation. CB2 agonists could potentially address both viral persistence and neuroinflammation, two major challenges in HIV-associated neurocognitive disorders.

The cell-type specificity of CB2 agonist effects is important for drug development: a single CB2-targeted therapy may work differently in different brain cell types, which could have both beneficial and unexpected consequences.

In vitro study using isolated cell types, not the complex brain environment. iPSC-derived microglia may not fully recapitulate primary microglia. Single CB2 agonist tested. No in vivo validation. HIV strain specificity not assessed.