EXPLORING THE EFFECT OF CBD/THC ON A PRIMARY MICROGLIA-LIKE CELL MODEL DURING HIV-1 INFECTION

Infection of microglia by macrophage-tropic HIV-1 within the central nervous system (CNS) is thought to contribute to persistent neuroinflammation and the development of HIV-associated neurocognitive disorders (HAND). Although cannabinoids such as Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD) are widely used by people living with HIV-1, their effects on early HIV-1 infection in microglia remain poorly defined. Here, we use a primary human monocyte-derived microglia (MDMi) model to examine how cannabinoids impact HIV-1 replication and host transcriptional responses during early post-entry events. We show that HIV-1 infection in MDMi is productive over 36 hours, with reverse transcription and integration largely completed within 12 hours post infection. Canonical inflammatory stimuli (IFN-α, IFN-γ, or LPS) potently restricted HIV-1 infection, demonstrating the capacity of MDMi to mount antiviral responses early in infection. Both CBD and THC significantly reduced HIV-1 expression without inducing cytotoxicity, and they engaged functional cannabinoid signaling, as evidenced by decreased intracellular cAMP. Transcriptomic profiling revealed that cannabinoid treatment during early infection induced distinct host transcriptional states, with CBD and THC differentially modulating interferon responses and inflammatory signaling. Notably, cannabinoid-dependent effects were evident only in the context of HIV-1 infection, indicating that cannabinoid effects are context dependent and emerge specifically during HIV-1 infection rather than in basal transcription. Together, these findings identify an early window during which HIV-1 replication in microglia is highly sensitive to immunomodulatory signals and reveal distinct effects of CBD and THC on viral replication and inflammatory programming in a physiologically relevant human microglial-like cell model.