Mini-review: The therapeutic role of cannabinoids in neuroHIV

Abstract

In the era of combined antiretroviral therapy (cART), human immunodeficiency virus type 1 (HIV-1) is considered a chronic disease with an inflammatory component that specifically targets the brain and causes a high prevalence of HIV-1-associated neurocognitive disorders (HAND). The endocannabinoid (eCB) system has attracted interest as a target for treatment of neurodegenerative disorders, due to the potential anti-inflammatory and neuroprotective properties of cannabinoids, including its potential therapeutic use in HIV-1 neuropathogenesis. In this review, we summarize what is currently known about the structural and functional changes of the eCB system under conditions of HAND. This will be followed by summarizing the current clinical and preclinical findings on the effects of cannabis use and cannabinoids in the context of HIV-1 infection, with specifically focusing on viral load, cognition, inflammation, and neuroprotection. Lastly, we present some potential future directions to better understand the involvement of the eCB system and the role that cannabis use and cannabinoids play in neuroHIV.

Keywords: Antiretroviral therapy; C-C motif chemokine receptor 5 (CCR5); C-X-C motif chemokine receptor 4 (CXCR4); Cannabinoid type 1 receptor; Cannabinoid type 2 receptor; Cannabis; Endogenous cannabinoid system; Fatty acid amide hydrolase; G-protein coupled receptor (GPCR) GPR18; HIV-associated neurocognitive disorders; Inflammation; MJN110; Microglia; Monoacylglycerol lipase; Neurodegeneration; PF3845; Synaptodendritic degeneration; neuroHIV; Δ(9)-tetrahydrocannabinol.

Figure 1.

A schematic presentation of the endocannabinoid (eCB) system. (A) Represents the eCB system in a healthy individual. CB₁Rs are present on presynaptic neurons. The influx of Ca²⁺ into the presynaptic neuron causes release of glutamate in the synapse and interacts with postsynaptic receptors (i.e. NMDR, mGluR). Excess of glutamate is taken up by the glutamate transporter present on astrocytes. CB₁R agonists block the release of glutamate and decrease excitotoxicity. CB₂Rs are predominantly expressed on microglia and their activation by CB₂R agonists decreases neuroinflammation by blocking the production of proinflammatory cytokines. It has been shown that neurons, but also glial cells, produce eCBs AEA and 2-AG which are hydrolyzed by the enzymes MAGL and FAAH, respectively. (B) Shows the possible mechanism of action of Tat and its effects on the eCB system in PWH. (1) Tat causes an excess of glutamate release into the synapse and (2) abnormally increases Ca²⁺ influx by acting on the NMDR, VGCC, and TRPC. (3) Tat blocks the glutamate transporter which further increases glutamate concentration in the synapse. TRPC channel is a non-selective cation channel that is also permeable for Ca²⁺. (4) Tat increases the IP₃ concentration which activates the TRPC and leads to Ca²⁺. Additionally, the increased IP₃ levels cause intracellular Ca²⁺ release from the ER. This excess of intracellular Ca²⁺ concentration causes Ca²⁺ overload, Ca²⁺ dysregulation, oxidative stress which leads to neuronal injury and eventually neuronal death. Tat also leads to the upregulation of CB₁Rs and CB₂Rs. Even though the CB₁R is upregulated in the presynaptic neuron, it is currently debated whether its inhibitory function is impaired or enhanced (represented by the broken inhibitor line). The negative effects of Tat are counteracted at the microglia as the overexpression of CB₂R blocks proinflammatory cytokines more effectively. Whether the endogenous ligands AEA and 2-AG are affected by Tat and their levels are upregulated in the brain of PWH is still not known (represented by ?). Abbreviations; 2-AG, 2-arachidonoylglycerol; AA, arachidonic acid; AEA, arachidonoyl ethanolamine (anandamide); Ca²⁺, calcium; DAG, diacylglycerol; DGL, diacylglycerol lipase; eCB, endocannabinoid; EA, ethanolamine; ER, endoplasmic reticulum; FAAH, fatty acid amide hydrolase; IP₃, inositol triphosphate; mGluR, metabotropic glutamate receptor; MAGL, monoacylglycerol lipase; NAPE-PLD, N-arachidonoyl phosphatidylethanolamine phospholipase D; NAPE, N-arachidonoyl phosphatidylethanolamine; NMDR, N-methyl-D-aspartate receptor; PE, phosphatidylethanolamine; PIP₂, phosphatidylinositol 4,5-bisphosphate; PLC, phospholipase C; PWH, people living with HIV; Tat, transactivator of transcription; TRPC, transient receptor potential cation channel; VGCC, voltage-gated calcium channel. Created with BioRender.com.